HCV NS3 protease inhibitors

ABSTRACT

The present invention relates to macrocyclic compounds of formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is claims the benefit under 35 U.S.C. 119(e) of U.S.Provisional Application No. 60/700,764 filed on Jul. 20, 2005 and60/724,566 filed on Oct. 7, 2005.

The present invention relates to macrocyclic compounds that are usefulas inhibitors of the hepatitis C virus (HCV) NS3 protease, theirsynthesis, and their use for treating or preventing HCV infection.

BACKGROUND OF THE INVENTION

Hepatitis C virus (HCV) infection is a major health problem that leadsto chronic liver disease, such as cirrhosis and hepatocellularcarcinoma, in a substantial number of infected individuals, estimated tobe 2-15% of the world's population. There are an estimated 3.9 millioninfected people in the United States alone, according to the U.S. Centerfor Disease Control, roughly five times the number of people infectedwith the human immunodeficiency virus (HIV). According to the WorldHealth Organization, there are more than 170 million infectedindividuals worldwide, with at least 3 to 4 million people beinginfected each year. Once infected, about 20% of people clear the virus,but the rest harbor HCV the rest of their lives. Ten to twenty percentof chronically infected individuals eventually develop liver-destroyingcirrhosis or cancer. The viral disease is transmitted parenterally bycontaminated blood and blood products, contaminated needles, or sexuallyand vertically from infected mothers or carrier mothers to theiroff-spring.

Current treatments for HCV infection, which are restricted toimmunotherapy with recombinant interferon-a alone or in combination withthe nucleoside analog ribavirin, are of limited clinical benefit.Moreover, there is no established vaccine for HCV. Consequently, thereis an urgent need for improved therapeutic agents that effectivelycombat chronic HCV infection. The current state of the art in thetreatment of HCV infection has been discussed in the followingreferences: B. Dymock, et al., “Novel approaches to the treatment ofhepatitis C virus infection,” Antiviral Chemistry & Chemotherapy, 11:79-96 (2000); H. Rosen, et al., “Hepatitis C virus: currentunderstanding and prospects for future therapies,” Molecular MedicineToday, 5: 393-399 (1999); D. Moradpour, et al., “Current and evolvingtherapies for hepatitis C,” European J. Gastroenterol. Hepatol., 11:1189-1202 (1999); R. Bartenschlager, “Candidate Targets for Hepatitis CVirus-Specific Antiviral Therapy,” Intervirology, 40: 378-393 (1997); G.M. Lauer and B. D. Walker, “Hepatitis C Virus Infection,” N. Engl. J.Med., 345: 41-52 (2001); B. W. Dymock, “Emerging therapies for hepatitisC virus infection,” Emerging Drugs, 6: 13-42 (2001); and C. Crabb,“Hard-Won Advances Spark Excitement about Hepatitis C,” Science: 506-507(2001).

Several virally-encoded enzymes are putative targets for therapeuticintervention, including a metalloprotease (NS2-3), a serine protease(NS3), a helicase (NS3), and an RNA-dependent RNA polymerase (NS5B). TheNS3 protease is located in the N-terminal domain of the NS3 protein, andis considered a prime drug target since it is responsible for anintramolecular cleavage at the NS3/4A site and for downstreamintermolecular processing at the NS4A/4B, NS4B/5A and NS5A/5B junctions.Previous research has identified classes of peptides, such ashexapeptides as well as tripeptides discussed in U.S. patentapplications US2005/0020503, US2004/0229818, and US2004/00229776,showing degrees of activity in inhibiting the NS3 protease. The aim ofthe present invention is to provide further compounds which exhibitactivity against the HCV NS3 protease.

SUMMARY OF THE INVENTION

The present invention relates to novel macrocyclic compounds of formula(I) and/or pharmaceutically acceptable salts or hydrates thereof. Thesecompounds are useful in the inhibition of HCV (hepatitis C virus) NS3(non-structural 3) protease, the prevention or treatment of one or moreof the symptoms of HCV infection, either as compounds or theirpharmaceutically acceptable salts or hydrates (when appropriate), or aspharmaceutical composition ingredients, whether or not in combinationwith other HCV antivirals, anti-infectives, immunomodulators,antibiotics or vaccines. More particularly, the present inventionrelates to a compound of formula (I) and/or a pharmaceuticallyacceptable salt or hydrate thereof:

wherein:

-   p and q are independently 1 or 2;-   R¹ is CO₂R¹⁰, CONR¹⁰SO₂R⁶, CONR¹⁰SO₂NR⁸R⁹, or tetrazolyl;-   R² is C₁-C₆ alkyl, C₂-C₆ alkenyl or C₃-C₈ cycloalkyl, wherein said    alkyl, alkenyl or cycloalkyl is optionally substituted with 1 to 3    halo;-   R³ is C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyl(C₁-C₈)alkyl,    aryl(C₁-C₈)alkyl, or Het, wherein aryl is phenyl or naphthyl and    said alkyl, cycloalkyl, or aryl is optionally substituted with 1 to    3 substituents selected from the group consisting of halo, OR¹⁰,    SR¹⁰, N(R¹⁰)₂, N(C₁-C₆ alkyl)O(C₁-C₆ alkyl), C₁-C₆ alkyl, C₁-C₆    haloalkyl, halo(C₁-C₆ alkoxy), NO₂, CN, CF₃, SO₂(C₁-C₆ alkyl),    S(O)(C₁-C₆ alkyl), NR¹⁰SO₂R⁶, SO₂N(R⁶)₂, NHCOOR⁶, NHCOR⁶, NHCONHR⁶,    CO₂R¹⁰, C(O)R¹⁰, and CON(R¹⁰)₂;-   Het is a 5- or 6-membered saturated cyclic ring having 1 or 2    heteroatoms selected from N, O and S, wherein said ring is    optionally substituted with 1 to 3 substituents selected from halo,    OR¹⁰, SR¹⁰, N(R¹⁰)₂, N(C₁-C₆ alkyl)O(C₁-C₆ alkyl), C₁-C₆ alkyl,    C₁-C₆ haloalkyl, halo(C₁-C₆ alkoxy), NO₂, CN, CF₃, SO₂(C₁-C₆ alkyl),    S(O)(C₁-C₆ alkyl), NR¹⁰SO₂R⁶, SO₂N(R⁶ ₂, NHCOOR⁶, NHCOR⁶, NHCONHR⁶,    CO₂R¹⁰, C(O)R¹⁰, and CON(R¹⁰)₂;-   R⁴ is H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl(C₁-C₈)alkyl, or    aryl(C₁-C₈)alkyl; wherein aryl is phenyl or naphthyl and said alkyl,    cycloalkyl, or aryl is optionally substituted with 1 to 3    substituents selected from the group consisting of halo, OR¹⁰, SR¹⁰,    N(R¹⁰)₂, N(C₁-C₆ alkyl)O(C₁-C₆ alkyl), C₁-C₆ alkyl, C₁-C₆ haloalkyl,    halo(C₁-C₆ alkoxy), NO₂, CN, CF₃, SO₂(C₁-C₆ alkyl), S(O)(C₁-C₆    alkyl), NR¹⁰SO₂R⁶, SO₂N(R⁶)₂, NHCOOR⁶, NHCOR⁶, NHCONHR⁶, CO₂R¹⁰,    C(O)R¹⁰, and CON(R¹⁰)₂;-   R⁵ is H, halo, OR¹⁰, C₁-C₆ alkyl, CN, CF₃, SR¹⁰, SO₂(C₁-C₆ alkyl),    C₃-C₈ cycloalkyl, C₃-C₈ cycloalkoxy, C₁-C₆ haloalkyl, N(R⁷)₂, aryl,    heteroaryl or heterocyclyl; wherein aryl is phenyl or naphthyl,    heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3    heteroatoms selected from N, O and S, attached through a ring carbon    or nitrogen, and heterocyclyl is a 5- to 7-membered saturated or    unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms    selected from N, O and S, attached through a ring carbon or    nitrogen; and wherein said aryl, heteroaryl, heterocyclyl,    cycloalkyl, cycloalkoxy, alkyl or alkoxy is optionally substituted    with 1 to 4 substituents selected from the group consisting of halo,    OR¹⁰, SR¹⁰, N(R⁷)₂, N(C₁-C₆ alkyl)O(C₁-C₆ alkyl), C₁-4C₆ alkyl,    C₁-C₆ haloalkyl, halo(C₁-C₆ alkoxy), C₃-C₆ cycloalkyl, C₃-C₆    cycloalkoxy, NO₂, CN, CF₃, SO₂(C₁-C₆ alkyl), NR¹⁰SO₂R⁶, SO₂N(R⁶)₂,    S(O)C₁-C₆ alkyl), NHCOOR⁶, NHCOR⁶, NHCONHR⁶, CO₂R¹⁰, C(O)R¹⁰, and    CON(R¹⁰)₂; wherein 2 adjacent substituents of said cycloalkyl,    cycloalkoxy, aryl, heteroaryl or heterocyclyl are optionally taken    together to form a 3to -6-membered cyclic ring containing 0-3    heteroatoms selected from N, O and S;-   R⁶ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl(C₁-C₅)alkyl,    aryl, aryl(C₁-C₄)alkyl, heteroaryl, heteroaryl(C₁-C₄ alkyl),    heterocyclyl, or heterocyclyl(C₁-C₈ alkyl), wherein said alkyl,    cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally    substituted with 1 to 2 W substituents; and wherein each aryl is    independently phenyl or naphthyl, each heteroaryl is independently a    5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected    from N, O and S, attached through a ring carbon or nitrogen, and    each heterocyclyl is independently a 5- to 7-membered saturated or    unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms    selected from N, O and S, attached through a ring carbon or    nitrogen;-   Y is C(═O), SO₂, or C(═N—CN);-   Z is C(R¹⁰)₂, O, or N(R⁴);-   M is C₁-C₁₂ alkylene or C₂-C₁₂ alkenylene, wherein said alkylene or    alkenylene is optionally substituted with 1 or 2 substituents    selected from the group consisting of C₁-C₈ alkyl, C₃-C₈    cycloalkyl(C₁-C₈ alkyl), and aryl(C₁-C₈ alkyl); and 2 adjacent    substituents of M are optionally taken together to form a 3- to    6-membered cyclic ring containing 0-3 heteroatoms selected from N, O    and S;-   each R⁷ is independently H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆    cycloalkyl(C₁-C₅)alkyl, aryl, aryl(C₁-C₄)alkyl, heteroaryl,    heteroaryl(C₁-C₄ alkyl), heterocyclyl, or heterocyclyl(C₁-C₈ alkyl),    wherein said alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is    optionally substituted with 1 to 2 W substituents; and wherein each    aryl is independently phenyl or naphthyl, each heteroaryl is    independently a 5- or 6-membered aromatic ring having 1, 2 or 3    heteroatoms selected from N, O and S, attached through a ring carbon    or nitrogen, and each heterocyclyl is independently a 5- to    7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3    or 4 heteroatoms selected from N, O and S, attached through a ring    carbon or nitrogen;-   each W is independently halo, OR¹⁰, C₁-C₆ alkyl, CN, CF₃, NO₂, SR¹⁰,    CO₂R¹⁰, CON(R¹⁰)₂, C(O)R¹⁰, N(R¹⁰)C(O)R¹⁰, SO₂(C₁-C₆ alkyl),    S(O)(C₁-C₆ alkyl), C₃-C₈ cycloalkyl, C₃-C₈ cycloalkoxy, C₁-C₆    haloalkyl, N(R¹⁰)₂, N(C₁-C₆ alkyl)O(C₁-C₆ alkyl), halo(C₁-C₆    alkoxy), NR¹⁰SO₂R¹⁰, SO₂N(R¹⁰)₂, NHCOOR¹⁰, NHCONHR¹⁰, aryl,    heteroaryl or heterocyclyl; wherein aryl is phenyl or naphthyl,    heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3    heteroatoms selected from N, O and S, attached through a ring carbon    or nitrogen, and heterocyclyl is a 5- to 7-membered saturated or    unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms    selected from N, O and S, attached through a ring carbon or    nitrogen;-   R⁸ is C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyl(C₁-C₈ alkyl),    aryl, aryl(C₁-C₄ alkyl), heteroaryl, heterocyclyl, heteroaryl(C₁-C₄    alkyl), or heterocyclyl(C₁-C₈ alkyl), wherein said alkyl,    cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally    substituted with 1 to 4 substituents selected from the group    consisting of aryl, C₃-C₈ cycloalkyl, heteroaryl, heterocyclyl,    C₁-C₆ alkyl, halo(C₁-C₆ alkoxy), halo, OR¹⁰, SR¹⁰, N(R¹⁰)₂, N(C₁-C₆    alkyl)O(C₁-C₆ alkyl), C₁-C₆ alkyl, C(O)R¹⁰, C₁-C₆ haloalkyl, NO₂,    CN, CF₃, SO₂(C₁-C₆ alkyl), S(O)(C₁-C₆ alkyl), NR¹⁰SO₂R⁶, SO₂N(R⁶)₂,    NHCOOR⁶, NHCOR⁶, NHCONHR⁶, CO₂R¹⁰, and C(O)N(R¹⁰)₂; wherein each    aryl is independently phenyl or naphthyl; each heteroaryl is    independently a 5- or 6-membered aromatic ring having 1, 2 or 3    heteroatoms selected from N, O and S, attached through a ring carbon    or nitrogen; and each heterocyclyl is independently a 5- to    7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3    or 4 heteroatoms selected from N, O and S, attached through a ring    carbon or nitrogen; and wherein 2 adjacent substituents of said    cycloalkyl, cycloalkoxy, aryl, heteroaryl or heterocyclyl are    optionally taken together to form a 3- to 6-membered cyclic ring    containing 0-3 heteroatoms selected from N, O and S;-   R⁹ is C₁-C₈ alkyl, C₃-C8 cycloalkyl, C₃-C₈ cycloalkyl(C₁-C₈ alkyl),    C₁-C₈ alkoxy, C₃-C₈ cycloalkoxy, aryl, aryl(C₁-C₄ alkyl),    heteroaryl, heterocyclyl, heteroaryl(C₁-C₄ alkyl), or    heterocyclyl(C₁-C₈ alkyl), wherein said alkyl, cycloalkyl, alkoxy,    cycloalkoxy, aryl, heteroaryl or heterocyclyl is optionally    substituted with 1 to 4 substituents selected from the group    consisting of aryl, C₃-C₈ cycloalkyl, heteroaryl, heterocyclyl,    C₁-C₆ alkyl, halo(C₁-C₆ alkoxy), halo, OR¹⁰, SR¹⁰, N(R¹⁰)₂, N(C₁-C₆    alkyl)O(C₁-C₆ alkyl), C₁-C₆ alkyl, C(O)R¹⁰, C₁-C₆ haloalkyl, NO₂,    CN, CF₃, SO₂(C₁-C₆ alkyl), S(O)(C₁-C₆ alkyl), NR¹⁰SO₂R⁶, SO₂N(R⁶)₂,    NHCOOR⁶, NHCOR⁶, NHCONHR⁶, CO₂R¹⁰, and C(O)N(R¹⁰)₂; wherein each    aryl is independently phenyl or naphthyl; each heteroaryl is    independently a 5- or 6-membered aromatic ring having 1, 2 or 3    heteroatoms selected from N, O and S, attached through a ring carbon    or nitrogen; and each heterocyclyl is independently a 5- to    7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3    or 4 heteroatoms selected from N, O and S, attached through a ring    carbon or nitrogen; and wherein 2 adjacent substituents of said    cycloalkyl, cycloalkoxy, aryl, heteroaryl or heterocyclyl are    optionally taken together to form a 3- to 6-membered cyclic ring    containing 0-3 heteroatoms selected from N, O and S;-   or R⁸ and R⁹ are optionally taken together, with the nitrogen atom    to which they are attached, to form a 4- to 8-membered monocyclic    ring containing 0-2 additional heteroatoms selected from N, O and S;    and-   each R¹⁰ is independently H or C₁-C₆ alkyl.

The present invention also includes pharmaceutical compositionscontaining a compound of the present invention and methods of preparingsuch pharmaceutical compositions. The present invention further includesmethods of treating or preventing one or more symptoms of HCV infection.

Other embodiments, aspects and features of the present invention areeither further described in or will be apparent from the ensuingdescription, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes compounds of formula I above, andpharmaceutically acceptable salts and/or hydrates thereof. Thesecompounds and their pharmaceutically acceptable salts and/or hydratesare HCV protease inhibitors (e.g., HCV NS3 protease inhibitors). Thepresent invention also includes compounds of formulae II, II-a, II-b,II-c, II-d, III, III-a, III-b, III-c, and III-d wherein all variablesare as defined for formula I.

A first embodiment of the present invention is a compound of formula I,II, II-a, II-b, II-c, II-d, III, III-a, III-b, III-c, or III-d, or apharmaceutically acceptable salt or hydrate thereof, wherein R¹ isCO₂R¹⁰ or CONR¹⁰SO₂R⁶, and all other variables are as originally defined(i.e., as defined in the Summary of the Invention). In a first aspect ofthe first embodiment, R¹ is CONR¹⁰SO₂R⁶; and all other variables are asdefined in the first embodiment. In a feature of the first aspect of thefirst embodiment, R¹ is CONHSO₂R⁶ wherein R⁶ is C₃-C₈ cycloalkyl; andall other variables are as defined in the first embodiment. In a secondfeature of the first aspect of the first embodiment, R¹ is CONHSO₂R⁶wherein R⁶ is cyclopropyl; and all other variables are as defined in thefirst embodiment. In a second aspect of the first embodiment, R¹ isCO₂R¹⁰; and all other variables are as defined in the first embodiment.In a feature of the second aspect of the first embodiment, R¹ is CO₂H;and all other variables are as defined in the first embodiment.

A second embodiment of the present invention is a compound of formula I,II, II-a, II-b, II-c, II-d, III, III-a, III-b, III-c, or III-d, or apharmaceutically acceptable salt or hydrate thereof, wherein R¹ isCONHSO₂NR⁸R⁹; and all other variables are as originally defined. In afirst aspect of the second embodiment, R⁸ is C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkyl(C₁-C₈ alkyl), aryl, aryl(C₁-C₄ alkyl),heteroaryl, or heteroaryl(C₁-C₄ alkyl); and R⁹ is C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkyl(C₁-C₈ alkyl), C₁-C₈ alkoxy, aryl,aryl(C₁-C₄ alkyl), heteroaryl, or heteroaryl(C₁-C₄ alkyl), wherein saidalkyl, cycloalkyl, alkoxy, aryl, or heteroaryl in both R⁸ and R⁹ isoptionally substituted with 1 to 4 substituents selected from the groupconsisting of aryl, heteroaryl, C₁-C₆ alkyl, halo(C₁-C₆ alkoxy), halo,OR¹⁰, SR¹⁰, N(R¹⁰)₂, N(C₁-C₆ alkyl)O(C₁-C₆ alkyl), C₁-C₆ alkyl, C(O)R¹⁰,C₁-C₆ haloalkyl, NO₂, CN, CF₃, SO₂(C₁-C₆ alkyl), S(O)(C₁-C₆ alkyl),NR¹⁰SO₂R⁶, SO₂N(R⁶)₂, NHCOOR⁶, NHCOR⁶, NHCONHR⁶, CO₂R¹⁰, andC(O)N(R¹⁰)₂, wherein each aryl is independently phenyl or naphthyl andeach heteroaryl is independently a 5- or 6-membered aromatic ring having1, 2 or 3 heteroatoms selected from N, O and S, attached through a ringcarbon or nitrogen, and wherein 2 adjacent substituents of saidcycloalkyl, aryl, or heteroaryl are optionally taken together to form a3- to 6-membered cyclic ring containing 0-3 heteroatoms selected from N,O and S; or R⁸ and R⁹ are optionally taken together, with the nitrogenatom to which they are attached, to form a 4- to 8-membered monocyclicring containing 0-2 additional heteroatoms selected from N, O and S; andall other variables are as defined in the second embodiment.

In a second aspect of the second embodiment, R⁸ is C₁-C₈ alkyl, C₃-C₈cycloalkyl(C₁-C₈ alkyl), aryl, aryl(C₁-C₄ alkyl), heteroaryl, orheteroaryl(C₁-C₄ alkyl); and R⁹ is C₁-C₈ alkyl, C₃-C₈ cycloalkyl(C₁-C₈alkyl), C₁-C₈ alkoxy, aryl, aryl(C₁-C₄ alkyl), heteroaryl, orheteroaryl(C₁-C₄ alkyl), wherein said alkyl, cycloalkyl, alkoxy, aryl,or heteroaryl in both R⁸ and R⁹ is optionally substituted with 1 to 4substituents selected from the group consisting of aryl, C₃-C₈cycloalkyl, heteroaryl, heterocyclyl, C₁-C₆ alkyl, halo(C₁-C₆ alkoxy),halo, OR¹⁰, SR¹⁰, N(R¹⁰)₂, N(C₁-C₆ alkyl)O(C₁-C₆ alkyl), C₁-C₆ alkyl,C(O)R¹⁰, C₁-C₆ haloalkyl, NO₂, CN, CF₃, SO₂(C₁-C₆ alkyl), S(O)(C₁-C₆alkyl), NR¹⁰SO₂R⁶, SO₂N(R⁶)₂, NHCOOR⁶, NHCOR⁶, NHCONHR⁶, CO₂R¹⁰, andC(O)N(R¹⁰)₂, wherein each aryl is independently phenyl or naphthyl andeach heteroaryl is independently a 5- or 6-membered aromatic ring having1, 2 or 3 heteroatoms selected from N, O and S, attached through a ringcarbon or nitrogen, and wherein 2 adjacent substituents of saidcycloalkyl, aryl, or heteroaryl are optionally taken together to form 3-to 6-membered cyclic ring containing 0-3 heteroatoms selected from N, Oand S; or R⁸ and R⁹ are optionally taken together, with the nitrogenatom to which they are attached, to form a 4- to 6-membered monocyclicring containing 0-2 additional heteroatoms selected from N, O and S; andall other variables are as defined in the second embodiment.

In a first feature of the second aspect of the second embodiment, R⁸ isC₁-C₃ alkyl, wherein said alkyl is optionally substituted with 1 to 3substituents selected from the group consisting of halo, OR¹⁰, SR¹⁰,N(R¹⁰)₂, N(C₁-C₆ alkyl)O(C₁-C₆ alkyl), C₁-C₆ alkyl, C(O)R¹⁰, C₁-C₆haloalkyl, NO₂, CN, CF₃, SO₂(C₁-C₆ alkyl), S(O)(C₁-C₆ alkyl), NR¹⁰SO₂R⁶,SO₂N(R⁶)₂, NHCOOR⁶, NHCOR⁶, NHCONHR⁶, CO₂R¹⁰, and C(O)N(R¹⁰)₂; and R⁹ isC₁-C₃ alkyl, C₁-C₃ alkoxy, phenyl, or —(CH₂)₁₋₂-phenyl, wherein saidalkyl or alkoxy is optionally substituted with 1 to 3 substituentsselected from the group consisting of halo, OR¹⁰, SR¹⁰, N(R¹⁰)₂, N(C₁-C₆alkyl)O(C₁-C₆ alkyl), C₁-C₆ alkyl, C(O)R¹⁰, C₁-C₆ haloalkyl, NO₂, CN,CF₃, SO₂(C₁-C₆ alkyl), S(O)(C₁-C₆ alkyl), NR¹⁰SO₂R⁶, SO₂N(R⁶)₂, NHCOOR⁶,NHCOR⁶, NHCONHR⁶, CO₂R¹⁰, and C(O)N(R¹⁰)₂; or R⁸ and R⁹ are optionallytaken together, with the nitrogen atom to which they are attached, toform a 4- to 6-membered monocyclic saturated ring containing 0-1additional heteroatoms selected from N and O; and all other variablesare as defined in the second embodiment. In a second feature of thesecond aspect of the second embodiment, R⁸ is methyl; and all othervariables are as defined in the second embodiment. In a third feature ofthe second aspect of the second embodiment, R⁹ is methyl, methoxy,ethyl, i-propyl, phenyl, or benzyl; and all other variables are asdefined in the second embodiment. In a fourth feature of the secondaspect of the second embodiment, R⁸ and R⁹ are taken together to form aheteocyclic ring selected from the following:

and all other variables are as defined in the second embodiment. In afifth feature of the second aspect of the second embodiment, R⁸ ismethyl and R⁹ is methoxy; and all other variables are as defined in thesecond embodiment.

A third embodiment of the present invention is a compound of formula I,II, II-a, II-b, II-c, II-d, III, III-a, III-b, III-c, or III-d, or apharmaceutically acceptable salt or hydrate thereof, wherein R² is C₁-C₆alkyl or C₂-C₆ alkenyl; and all other variables are as originallydefined or as defined in any one of the preceding embodiments. In afirst aspect of the third embodiment, R² is C₁-C₄ alkyl or C₂-C₄alkenyl; and all other variables are as originally defined or as definedin any one of the preceding embodiments. In a second aspect of the thirdembodiment, R² is C₂-C₄ alkenyl; and all other variables are asoriginally defined or as defined in any one of the precedingembodiments. In a feature of the second aspect of the third embodiment,R² is vinyl; and all other variables are as defined in the secondembodiment or as defined in any one of the preceding embodiments. In athird aspect of the third embodiment, R² is C₁-C₄ alkyl; and all othervariables are as originally defined or as defined in any one of thepreceding embodiments. In a feature of the third aspect of the thirdembodiment, R² is ethyl; and all other variables are as defined in thethird embodiment or as defined in any one of the preceding embodiments.

A fourth embodiment of the present invention is a compound of formula I,II, II-a, II-b, II-c, II-d, III, III-a, III-b, III-c, or III-d, or apharmaceutically acceptable salt or hydrate thereof, wherein R³ is C₃-C₈cycloalkyl optionally substituted with C₁-C₆ alkyl; Het; or C₁-C₈ alkyloptionally substituted with 1 to 3 substituents selected from halo andOR¹⁰; and all other variables are as originally defined or as defined inany one of the preceding embodiments. In a first aspect of the fourthembodiment, R³ is C₅-C₇ cycloalkyl, piperidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydropyranyl, or C₁-C₈ alkyl optionallysubstituted with 1 to 3 halo substituents; and all other variables areas defined in the fourth embodiment or as defined in any one of thepreceding embodiments. In a second aspect of the fourth embodiment, R³is C₅-C₆ cycloalkyl or C₁-C₈ alkyl optionally substituted with 1 to 3halo substituents; and all other variables are as defined in the fourthembodiment or as defined in any one of the preceding embodiments. In athird aspect of the fourth embodiment, R³ is propyl or butyl; and allother variables are as defined in the fourth embodiment or as defined inany one of the preceding embodiments. In a feature of the third aspectof the fourth embodiment, R³ is i-propyl, n-butyl or t-butyl; and allother variables are as defined in the fourth embodiment or as defined inany one of the preceding embodiments. In a fourth aspect of the fourthembodiment, R³ is cyclopentyl or cyclohexyl; and all other variables areas defined in the fourth embodiment or as defined in any one of thepreceding embodiments. In a fifth aspect of the fourth embodiment, R3 isCH₂CF₃ or CH₂CHF₂; and all other variables are as defined in the fourthembodiment or as defined in any one of the preceding embodiments. In asixth aspect of the fourth embodiment, R³ is C₃-C₈ cycloalkyl, Het, orCl-C₈ alkyl optionally substituted with 1 to 3 halo substituents; andall other variables are as originally defined or as defined in any oneof the preceding embodiments. In a seventh aspect of the fourthembodiment, R³ is C₃-C₈ cycloalkyl substituted with C₁-C₆ alkyl, orC₁-C₈ alkyl substituted with 1 to 3 OR¹⁰ substituents; and all othervariables are as originally defined or as defined in any one of thepreceding embodiments. In an eighth aspect of the fourth embodiment, R³is cyclohexyl substituted with methyl; and all other variables are asoriginally defined or as defined in any one of the precedingembodiments. In a nineth aspect of the fourth embodiment, R³ isCH₂O-t-Bu; and all other variables are as originally defined or asdefined in any one of the preceding embodiments.

A fifth embodiment of the present invention is a compound of formula I,II, II-a, II-b, II-c, II-d, III, III-a, III-b, III-c, or III-d, or apharmaceutically acceptable salt or hydrate thereof, wherein R⁵ is H orhalo; and all other variables are as originally defined or as defined inany one of the preceding embodiments. In one aspect of the fifthembodiment, R⁵ is H, F, or Cl; and all other variables are defined inthe fifth embodiment or as defined in any one of the precedingembodiments.

A sixth embodiment of the present invention is a compound of formula I,II, II-a, II-b, II-c, II-d, III, III-a, III-b, III-c, or III-d, or apharmaceutically acceptable salt or hydrate thereof, wherein R⁵ is C₁-C₆thioalkyl, aryl, heteroaryl, or heterocyclyl; wherein aryl is phenyl ornaphthyl, heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or3 heteroatoms selected from N, O and S, attached through a ring carbonor nitrogen, and heterocyclyl is a 5- to 7-membered saturated orunsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selectedfrom N, O and S, attached through a ring carbon or nitrogen; and whereinsaid aryl, heteroaryl, heterocyclyl, or thioalkyl is optionallysubstituted with 1 to 4 substituents selected from the group consistingof halo, OR¹⁰, SR¹⁰, N(R⁷)₂, N(C₁-C₆ alkyl)O(C₁-C₆ alkyl), C₁-C₆ alkyl,C₁-C₆ haloalkyl, halo(C₁-C₆ alkoxy), C₃-C₆ cycloalkyl, cycloalkoxy, NO₂,CN, CF₃, SO₂(C₁-C₆ alkyl), NR¹⁰SO₂R⁶, SO₂N(R⁶)₂, S(O)(C₁-C₆ alkyl),NHCOOR⁶, NHCOR⁶, NHCONHR⁶, CO₂R¹⁰, C(O)R¹⁰, and CON(R¹⁰)₂; and all othervariables are as originally defined or as defined in any one of thepreceding embodiments.

In one aspect of the sixth embodiment, R⁵ is aryl wherein aryl isoptionally substituted with 1 to 4 substituents selected from the groupconsisting of halo, OR¹⁰, SR¹⁰, N(R⁷)₂, N(C₁-C₆ alkyl)O(C₁-C₆ alkyl),C₁-C₆ alkyl, C₁-C₆ haloalkyl, halo(C₁-C₆ alkoxy), C₃-C₆ cycloalkyl,cycloalkoxy NO₂, CN, CF₃, SO₂(C₁-C₆ alkyl), NR¹⁰SO₂R⁶, SO₂N(R⁶)₂,S(O)(C₁-C₆ alkyl), NHCOOR⁶, NHCOR⁶, NHCONHR⁶, CO₂R¹⁰, C(O)R¹⁰, andCON(R¹⁰)₂; and all other variables are as defined in the sixthembodiment or as defined in any one of the preceding embodiments. In asecond aspect of the sixth embodiment, R⁵ is C₁-C₆ thioalkyl,

wherein R¹¹ is H, C₁-C₆ alkyl, NHR⁷, NHCOR¹², NHCONHR¹² or NHCOOR¹² andeach R¹² is independently C₁-C₆ alkyl or C₃-C₆ cycloalkyl; and all othervariables are as defined in the sixth embodiment or as defined in anyone of the preceding embodiments. In a third aspect of the sixthembodiment, R⁵ is

wherein R¹¹ is H, C₁-C₆ alkyl, NHR⁷, NHCOR¹², NHCONHR¹² or NHCOOR¹² andeach R¹² is independently C₁-C₆ alkyl or C₃-C₆ cycloalkyl; and all othervariables are as defined in the sixth embodiment or as defined in anyone of the preceding embodiments.

In a fourth aspect of the sixth embodiment, R⁵is unsubstituted phenyl;and all other variables are as defined in the sixth embodiment or asdefined in any one of the preceding embodiments.

A seventh embodiment of the present invention is a compound of formulaI, II, II-a, II-b, II-c, II-d, III, III-a, III-b, III-c, or III-d, or apharmaceutically acceptable salt or hydrate thereof, wherein R⁵ is C₁-C₆alkyl, C₁-C₆ alkoxy, hydroxy, or N(R⁷)₂ wherein R⁷is H or C₁-C₆ alkyl;and all other variables are as originally defined or as defined in anyone of the preceding embodiments. In one aspect of the seventhembodiment, R⁵ is C₁-C₆ alkoxy; and all other variables are as definedin the seventh embodiment or as defined in any one of the precedingembodiments. In a second aspect of the seventh embodiment, R⁵ ismethoxy; and all other variables are as defined in the seventhembodiment or as defined in any one of the preceding embodiments.

An eighth embodiment of the present invention is a compound of formulaI′, II′ or III′, or a pharmaceutically acceptable salt or hydratethereof, wherein all variables are as originally defined or as definedin any one of the preceding embodiments.

A ninth embodiment of the present invention is a compound of formula I,II, II-a, II-b, II-c, II-d, III, III-a, III-b, III-c, or III-d, or apharmaceutically acceptable salt or hydrate thereof, wherein Y is C═O orSO₂; and all other variables are as originally defined or as defined inany one of the preceding embodiments. In one aspect of the ninthembodiment, Y is C═O; and all other variables are as defined in theninth embodiment or as defined in any one of the preceding embodiments.

A tenth embodiment of the present invention is a compound of formula I,II, II-a, II-b, II-c, II-d, III, III-a, III-b, III-c, or III-d, or apharmaceutically acceptable salt or hydrate thereof, wherein Z is O,C(R¹⁰)₂, NH or N(C₁-C₈ alkyl); and all other variables are as originallydefined or as defined in any one of the preceding embodiments. In oneaspect of the tenth embodiment, Z is O, CH₂, NH, or N(CH₃); and allother variables are as defined in the tenth embodiment or as defined inany one of the preceding embodiments. In another aspect of the tenthembodiment, Z is N(i-Pr) or N(n-Pr); and all other variables are asdefined in the tenth embodiment or as defined in any one of thepreceding embodiments.

An eleventh embodiment of the present invention is a compound of formulaI, II, II-a, II-b, II-c, II-d, III, III-a, III-b, III-c, or III-d, or apharmaceutically acceptable salt or hydrate thereof, wherein M is C₁-C₈alkylene or C₂-C₈ alkenylene, wherein said alkylene or alkenylene isoptionally substituted with 1 or 2 substituents selected from C₁-C₈alkyl, C₃-C₈ cycloalkyl(C₁-C₈ alkyl), or aryl(C₁-C₈ alkyl); and the 2adjacent substituents of M are optionally taken together to form a 3- to6-membered cyclic ring containing 0-2 heteroatoms selected from N, O andS; and all other variables are as originally defined or as defined inany one of the preceding embodiments. In a first aspect of the eleventhembodiment, M is C₁-C₈ alkylene or C₂-C₈ alkenylene, wherein saidalkylene or alkenylene is optionally substituted with 1 or 2substituents selected from C₁-C₈ alkyl, C₃-C₈ cycloalkyl(C₁-C₈ alkyl),or aryl(C₁-C₈ alkyl); and all other variables are as originally definedor as defined in any one of the preceding embodiments. In a firstfeature of the first aspect of the eleventh embodiment, M isunsubstituted C₁-C₈ alkylene or unsubstituted C₂-C₈ alkenylene; and allother variables are as defined in the eleventh embodiment or as definedin any one of the preceding embodiments. In a second feature of thefirst aspect of the eleventh embodiment, M is unsubstituted C₄ alkyleneor unsubstituted C₄ alkenylene; and all other variables are as definedin the eleventh embodiment or as defined in any one of the precedingembodiments. In a third feature of the first aspect of the eleventhembodiment, M is unsubstituted C₅ alkylene or unsubstituted C₅alkenylene; and all other variables are as defined in the eleventhembodiment or as defined in any one of the preceding embodiments. In afourth feature of the first aspect of the eleventh embodiment, M isunsubstituted C₆ alkylene or unsubstituted C₆ alkenylene; and all othervariables are as defined in the eleventh embodiment or as defined in anyone of the preceding embodiments. In a fifth feature of the first aspectof the eleventh embodiment, M is unsubstituted C₇ alkylene orunsubstituted C₇ alkenylene; and all other variables are as defined inthe eleventh embodiment or as defined in any one of the precedingembodiments. In a sixth feature of the first aspect of the eleventhembodiment, M is unsubstituted C₈ alkylene or unsubstituted C₈alkenylene; and all other variables are as defined in the eleventhembodiment or as defined in any one of the preceding embodiments. In aseventh feature of the first aspect of the eleventh embodiment, M is:

In a second aspect of the eleventh embodiment, M is C₁-C₈ alkylene orC₂-C₈ alkenylene, wherein said alkylene or alkenylene is optionallysubstituted with 1 or 2 substituents selected from C₁-C₈ alkyl, C₃-C₈cycloalkyl(C₁-C₈ alkyl), or aryl(C₁-C₈ alkyl); and 2 adjacentsubstituents of M are taken together to form a 3- to 6-membered cyclicring containing 0 heteroatoms; and all other variables are as originallydefined or as defined in any one of the preceding embodiments.

A twelfth embodiment of the present invention is a compound, or apharmaceutically acceptable salt or hydrate thereof, selected from thegroup consisting of the compounds III-1 to III-240.

Other embodiments of the present invention include the following:

(a) A pharmaceutical composition comprising an effective amount of acompound of formula I, II, II-a, II-b, II-c, II-d, III, III-a, III-b,III-c, or III-d and a pharmaceutically acceptable carrier.

(b) The pharmaceutical composition of (a), further comprising a secondtherapeutic agent selected from the group consisting of a HCV antiviralagent, an immunomodulator, and an anti-infective agent.

(c) The pharmaceutical composition of (b), wherein the HCV antiviralagent is an antiviral selected from the group consisting of a HCVprotease inhibitor and a HCV NS5B polymerase inhibitor.

(d) A pharmaceutical combination which is (i) a compound of formula I,II, II-a, II-b, II-c, II-d, III, III-a, III-b, III-c, or III-d and (ii)a second therapeutic agent selected from the group consisting of a HCVantiviral agent, an immunomodulator, and an anti-infective agent;wherein the compound of formula I, II, II-a, II-b, II-c, II-d, III,III-a, III-b, III-c, or III-d and the second therapeutic agent are eachemployed in an amount that renders the combination effective forinhibiting HCV NS3 protease, or for treating or preventing infection byHCV.

(e) The combination of (d), wherein the HCV antiviral agent is anantiviral selected from the group consisting of a HCV protease inhibitorand a HCV NS5B polymerase inhibitor.

(f) A method of inhibiting HCV NS3 protease in a subject in need thereofwhich comprises administering to the subject an effective amount of acompound of formula I, II, II-a, II-b, II-c, II-d, III, III-a, III-b,III-c, or III-d.

(g) A method of preventing or treating infection by HCV in a subject inneed thereof which comprises administering to the subject an effectiveamount of a compound of formula I, II, II-a, II-b, II-c, II-d, III,III-a, III-b, III-c, or III-d.

(h) The method of (g), wherein the compound of formula I, II, II-a,II-b, H-c, II-d, III, III-a, III-b, III-c, or III-d is administered incombination with an effective amount of at least one second therapeuticagent selected from the group consisting of a HCV antiviral agent, animmunomodulator, and an anti-infective agent.

(i) The method of (h), wherein the HCV antiviral agent is an antiviralselected from the group consisting of a HCV protease inhibitor and a HCVNS5B polymerase inhibitor.

(j) A method of inhibiting HCV NS3 protease in a subject in need thereofwhich comprises administering to the subject the pharmaceuticalcomposition of (a), (b), or (c) or the combination of (d) or (e).

(k) A method of preventing or treating infection by HCV in a subject inneed thereof which comprises administering to the subject thepharmaceutical composition of (a), (b), or (c) or the combination of (d)or (e).

The present invention also includes a compound of the present invention(i) for use in, (ii) for use as a medicament for, or (iii) for use inthe preparation of a medicament for: (a) inhibiting HCV NS3 protease, or(b) preventing or treating infection by HCV. In these uses, thecompounds of the present invention can optionally be employed incombination with one or more second therapeutic agents selected from HCVantiviral agents, anti-infective agents, and immunomodulators.

Additional embodiments of the invention include the pharmaceuticalcompositions, combinations and methods set forth in (a)-(k) above andthe uses set forth in the preceding paragraph, wherein the compound ofthe present invention employed therein is a compound of one of theembodiments, aspects, classes, sub-classes, or features of the compoundsdescribed above. In all of these embodiments, the compound mayoptionally be used in the form of a pharmaceutically acceptable salt orhydrate as appropriate.

As used herein, the term “alkyl” refers to any linear or branched chainalkyl group having a number of carbon atoms in the specified range.Thus, for example, “C₁₋₆ alkyl” (or “C₁-C₆ alkyl”) refers to all of thehexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- andt-butyl, n- and isopropyl, ethyl and methyl. As another example, “C₁₋₄alkyl” refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl andmethyl.

The term “haloalkyl” refers to an alkyl group wherein a hydrogen hasbeen replaced by a halogen. The term “alkoxy” refers to an “alkyl-O—”group.

The term “alkylene” refers to any linear or branched chain alkylenegroup (or alternatively “alkanediyl”) having a number of carbon atoms inthe specified range. Thus, for example, “—C₁₋₆ alkylene-” refers to anyof the C₁ to C₆ linear or branched alkylenes. A class of alkylenes ofparticular interest with respect to the invention is —(CH₂)₁₋₆—, andsub-classes of particular interest include —(CH₂)₁₋₄—, —(CH₂)₁₋₃—,—(CH₂)₁₋₂—, and —CH₂—. Also of interest is the alkylene —CH(CH₃—.

The terms “cycloalkyl” refers to any cyclic ring of an alkane or alkenehaving a number of carbon atoms in the specified range. Thus, forexample, “C₃₋₈ cycloalkyl” (or “C₃-C₈ cycloalkyl”) refers tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. The term “cycloalkoxy” refers to a “cycloalkyl-O—” group.

The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine andiodine (alternatively referred to as fluoro, chloro, bromo, and iodo).

Unless expressly stated to the contrary, all ranges cited herein areinclusive. For example, a heteroaryl ring described as containing from“1 to 3 heteroatoms” means the ring can contain 1, 2, or 3 heteroatoms.It is also to be understood that any range cited herein includes withinits scope all of the sub-ranges within that range. The oxidized forms ofthe heteroatoms N and S are also included within the scope of thepresent invention.

When any variable (e.g., R⁷ and R¹⁰) occurs more than one time in anyconstituent or in formula I, II, II-a, II-b, II-c, II-d, III, III-a,III-b, III-c, or III-d or in any other formula depicting and describingcompounds of the invention, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

Unless expressly stated to the contrary, substitution by a namedsubstituent is permitted on any atom in a ring (e.g., aryl, aheteroaromatic ring, or a saturated heterocyclic ring) provided suchring substitution is chemically allowed and results in a stablecompound. A “stable” compound is a compound which can be prepared andisolated and whose structure and properties remain or can be caused toremain essentially unchanged for a period of time sufficient to allowuse of the compound for the purposes described herein (e.g., therapeuticor prophylactic administration to a subject).

As a result of the selection of substituents and substituent patterns,certain of the compounds of the present invention can have asymmetriccenters and can occur as mixtures of stereoisomers, or as individualdiastereomers, or enantiomers. All isomeric forms of these compounds,whether isolated or in mixtures, are within the scope of the presentinvention.

As would be recognized by one of ordinary skill in the art, certain ofthe compounds of the present invention can exist as tautomers. For thepurposes of the present invention a reference to a compound of formulaI, II, II-a, II-b, II-c, II-d, III, III-a, III-b, III-c, or III-d is areference to the compound per se, or to any one of its tautomers per se,or to mixtures of two or more tautomers.

The compounds of the present inventions are useful in the inhibition ofHCV protease (e.g., HCV NS3 protease) and the prevention or treatment ofinfection by HCV. For example, the compounds of this invention areuseful in treating infection by HCV after suspected past exposure to HCVby such means as blood transfusion, exchange of body fluids, bites,accidental needle stick, or exposure to patient blood during surgery.

The compounds of this invention are useful in the preparation andexecution of screening assays for antiviral compounds. For example, thecompounds of this invention are useful for isolating enzyme mutants,which are excellent screening tools for more powerful antiviralcompounds. Furthermore, the compounds of this invention are useful inestablishing or determining the binding site of other antivirals to HCVprotease, e.g., by competitive inhibition. Thus the compounds of thisinvention are commercial products to be sold for these purposes.

The compounds of the present invention may be administered in the formof pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” refers to a salt which possesses the effectiveness ofthe parent compound and which is not biologically or otherwiseundesirable (e.g., is neither toxic nor otherwise deleterious to therecipient thereof). Suitable salts include acid addition salts whichmay, for example, be formed by mixing a solution of the compound of thepresent invention with a solution of a pharmaceutically acceptable acidsuch as hydrochloric acid, sulfuric acid, acetic acid, trifluoroaceticacid, or benzoic acid. Many of the compounds of the invention carry anacidic moiety, in which case suitable pharmaceutically acceptable saltsthereof can include alkali metal salts (e.g., sodium or potassiumsalts), alkaline earth metal salts (e.g., calcium or magnesium salts),and salts formed with suitable organic ligands such as quaternaryammonium salts. Also, in the case of an acid (—COOH) or alcohol groupbeing present, pharmaceutically acceptable esters can be employed tomodify the solubility or hydrolysis characteristics of the compound.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention mean providing thecompound or a prodrug of the compound to the individual in need oftreatment. When a compound of the invention or a prodrug thereof isprovided in combination with one or more other active agents (e.g.,antiviral agents useful for treating HCV infection), “administration”and its variants are each understood to include concurrent andsequential provision of the compound or salt (or hydrate) and otheragents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients, as well as any productwhich results, directly or indirectly, from combining the specifiedingredients.

By “pharmaceutically acceptable” is meant that the ingredients of thepharmaceutical composition must be compatible with each other and notdeleterious to the recipient thereof.

The term “subject” (alternatively referred to herein as “patient”) asused herein refers to an animal, preferably a mammal, most preferably ahuman, who has been the object of treatment, observation or experiment.

The term “effective amount” as used herein means that amount of activecompound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician.In one embodiment, the effective amount is a “therapeutically effectiveamount” for the alleviation of the symptoms of the disease or conditionbeing treated. In another embodiment, the effective amount is a“prophylactically effective amount” for prophylaxis of the symptoms ofthe disease or condition being prevented. The term also includes hereinthe amount of active compound sufficient to inhibit HCV NS3 protease andthereby elicit the response being sought (i.e., an “inhibition effectiveamount”). When the active compound (i.e., active ingredient) isadministered as the salt, references to the amount of active ingredientare to the free acid or free base form of the compound.

For the purpose of inhibiting HCV NS3 protease and preventing ortreating HCV infection, the compounds of the present invention,optionally in the form of a salt or a hydrate, can be administered byany means that produces contact of the active agent with the agent'ssite of action. They can be administered by any conventional meansavailable for use in conjunction with pharmaceuticals, either asindividual therapeutic agents or in a combination of therapeutic agents.They can be administered alone, but typically are administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice. The compounds ofthe invention can, for example, be administered orally, parenterally(including subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques), by inhalation spray, orrectally, in the form of a unit dosage of a pharmaceutical compositioncontaining an effective amount of the compound and conventionalnon-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.Liquid preparations suitable for oral administration (e.g., suspensions,syrups, elixirs and the like) can be prepared according to techniquesknown in the art and can employ any of the usual media such as water,glycols, oils, alcohols and the like. Solid preparations suitable fororal administration (e.g., powders, pills, capsules and tablets) can beprepared according to techniques known in the art and can employ suchsolid excipients as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like. Parenteral compositions can beprepared according to techniques known in the art and typically employsterile water as a carrier and optionally other ingredients, such as asolubility aid. Injectable solutions can be prepared according tomethods known in the art wherein the carrier comprises a salinesolution, a glucose solution or a solution containing a mixture ofsaline and glucose. Further description of methods suitable for use inpreparing pharmaceutical compositions of the present invention and ofingredients suitable for use in said compositions is provided inRemington's Pharmaceutical Sciences, 18^(th) edition, edited by A. R.Gennaro, Mack Publishing Co., 1990.

The compounds of this invention can be administered orally in a dosagerange of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per dayin a single dose or in divided doses. One preferred dosage range is 0.01to 500 mg/kg body weight per day orally in a single dose or in divideddoses. Another preferred dosage range is 0.1 to 100 mg/kg body weightper day orally in single or divided doses. For oral administration, thecompositions can be provided in the form of tablets or capsulescontaining 1.0 to 500 milligrams of the active ingredient, particularly1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. The specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

As noted above, the present invention also relates to a method ofinhibiting HCV NS3 protease, inhibiting HCV replication, or preventingor treating HCV infection with a compound of the present invention incombination with one or more therapeutic agents and a pharmaceuticalcomposition comprising a compound of the present invention and one ormore therapeutic agents selected from the group consisting of a HCVantiviral agent, an immunomodulator, and an anti-infective agent. Suchtherapeutic agents active against HCV include, but are not limited to,ribavirin, levovirin, viramidine, thymosin alpha-1, R7025 (an enhancedinterferon (Roche)), interferon-β, interferon-α, pegylated interferon-α(peginterferon-α), a combination of interferon-α and ribavirin, acombination of peginterferon-α and ribavirin, a combination ofinterferon-α and levovirin, and a combination of peginterferon-α andlevovirin. Interferon-α includes, but is not limited to, recombinantinterferon-α2a (such as ROFERON interferon available fromHoffmann-LaRoche, Nutley, N.J.), pegylated interferon-α2a (PEGASYS™),interferon-α2b (such as INTRON-A interferon available from ScheringCorp., Kenilworth, N.J.), pegylated interferon-α2b (PEGIntron) arecombinant consensus interferon (such as interferon alphacon-1),albuferon (interferon-α bound to human serum albumin (Human GenomeSciences)), and a purified interferon-α product. Amgen's recombinantconsensus interferon has the brand name INFERGEN. Levovirin is theL-enantiomer of ribavirin which has shown immunomodulatory activitysimilar to ribavirin. Viramidine represents an analog of ribavirindisclosed in WO 01/60379 (assigned to ICN Pharmaceuticals). Inaccordance with the method of the present invention, the individualcomponents of the combination can be administered separately atdifferent times during the course of therapy or concurrently in dividedor single combination forms.

For the treatment of HCV infection, the compounds of the presentinvention may also be administered in combination with an agent that isan inhibitor of HCV NS3 serine protease. HCV NS3 serine protease is anessential viral enzyme and has been described to be an excellent targetfor inhibition of HCV replication. Both substrate and non-substratebased inhibitors of HCV NS3 protease inhibitors are disclosed in WO98/22496, WO 98/46630, WO 99/07733, WO 99/07734, WO 99/38888, WO99/50230, WO 99/64442, WO 00/09543, WO 00/59929, GB-2337262, WO02/48116, WO 02/48172, and U.S. Pat. No. 6,323,180.

Ribavirin, levovirin, and viramidine may exert their anti-HCV effects bymodulating intracellular pools of guanine nucleotides via inhibition ofthe intracellular enzyme inosine monophosphate dehydrogenase (IMPDH).IMPDH is the rate-limiting enzyme on the biosynthetic route in de novoguanine nucleotide biosynthesis. Ribavirin is readily phosphorylatedintracellularly and the monophosphate derivative is an inhibitor ofIMPDH. Thus, inhibition of IMPDH represents another useful target forthe discovery of inhibitors of HCV replication. Therefore, the compoundsof the present invention may also be administered in combination with aninhibitor of IMPDH, such as VX-497, which is disclosed in WO 97/41211and WO 01/00622 (assigned to Vertex); another IMPDH inhibitor, such asthat disclosed in WO 00/25780 (assigned to Bristol-Myers Squibb); ormycophenolate mofetil [see A. C. Allison and E. M. Eugui, Agents Action,44 (Suppl.): 165 (1993)].

For the treatment of HCV infection, the compounds of the presentinvention may also be administered in combination with the antiviralagent amantadine (1-aminoadamantane) [for a comprehensive description ofthis agent, see J. Kirschbaum, Anal. Profiles Drug Subs. 12: 1-36(1983)].

For the treatment of HCV infection, the compounds of the presentinvention may also be administered in combination with the antiviralagent polymerase inhibitor R7128 (Roche).

The compounds of the present invention may also be combined for thetreatment of HCV infection with antiviral 2′-C-branched ribonucleosidesdisclosed in R. E. Harry-O'kuru, et al., J. Org. Chem., 62: 1754-1759(1997); M. S. Wolfe, et al., Tetrahedron Lett., 36: 7611-7614 (1995);U.S. Pat. No. 3,480,613 (Nov. 25, 1969); International PublicationNumber WO 01/90121 (29 Nov. 2001); International Publication Number WO01/92282 (6 Dec. 2001); and International Publication Number WO 02/32920(25 Apr. 2002); and International Publication Number WO 04/002999 (8Jan. 2004); and International Publication Number WO 04/003000 (8 Jan.2004); and International Publication Number WO 04/002422 (8 Jan. 2004);the contents of each of which are incorporated by reference in theirentirety. Such 2′-C-branched ribonucleosides include, but are notlimited to, 2′-C-methyl-cytidine, 2′-C-methyl-uridine,2′-C-methyl-adenosine, 2′-C-methyl-guanosine, and9-(2-C-methyl-β-D-ribofuranosyl)-2,6-diaminopurine, and thecorresponding amino acid ester of the ribose C-2′, C-3′, and C-5′hydroxyls and the corresponding optionally substituted cyclic1,3-propanediol esters of the 5′-phosphate derivatives.

The compounds of the present invention may also be combined for thetreatment of HCV infection with other nucleosides having anti-HCVproperties, such as those disclosed in WO 02/51425 (4 Jul. 2002),assigned to Mitsubishi Pharma Corp.; WO 01/79246, WO 02/32920, WO02/48165 (20 Jun. 2002), and WO2005003147 (13 Jan. 2005)(includingR1656, (2′R)-2′-deoxy-2′-fluoro-2′-C-methylcytidine, methylcytidine,shown as compounds 3-6 on page 77) assigned to Pharmasset, Ltd.; WO01/68663 (20 Sep. 2001), assigned to ICN Pharmaceuticals; WO 99/43691 (2Sept. 1999); WO 02/18404 (7 Mar. 2002), US2005/0038240 (Feb. 17, 2005)and WO2006021341 (2 Mar. 2006), including 4′-azido nucleosides such asR1626, 4′-azidocytidine, assigned to Hoffmann-LaRoche; U.S. 2002/0019363(14 Feb. 2002); WO 02/100415 (19 Dec. 2002); WO 03/026589 (3 Apr. 2003);WO 03/026675 (3 Apr. 2003); WO 03/093290 (13 Nov. 2003);: US2003/0236216 (25 Dec. 2003); US 2004/0006007 (8 Jan. 2004); WO 04/011478(5 Feb. 2004); WO 04/013300 (12 Feb. 2004); US 2004/0063658 (1 Apr.2004); and WO 04/028481 (8 Apr. 2004); the content of each isincorporated herein by reference in its entirety.

For the treatment of HCV infection, the compounds of the presentinvention may also be administered in combination with an agent that isan inhibitor of HCV NS5B polymerase. Such HCV NS5B polymerase inhibitorsthat may be used as combination therapy include, but are not limited to,those disclosed in WO 02/057287, U.S. Pat. No. 6,777,395, WO 02/057425,US 2004/0067901, WO 03/068244, WO 2004/000858, WO 04/003138 and WO2004/007512; the content of each is incorporated herein by reference inits entirety. Other such HCV polymerase inhibitors include, but are notlimited to, valopicitabine (NM-283; Idenix) and2′-F-2′-beta-methylcytidine (see also WO 2005/003147, assigned toPharmasset, Ltd.).

In one embodiment, nucleoside HCV NS5B polymerase inhibitors that areused in combination with the present HCV NS3 protease inhibitors areselected from the following compounds:4-amino-7-(2-C-methyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-methylamino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-dimethylamino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-cyclopropylamino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-amino-7-(2-C-vinyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-amino-7-(2-C-hydroxymethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-amino-7-(2-C-fluoromethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-amino-5-methyl-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid;4-amino-5-bromo-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-amino-5-chloro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-amino-5-fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;2,4-diamino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;2-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;2-amino-4-cyclopropylamino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;2-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one;4-amino-7-(2-C-ethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-amino-7-(2-C,2-O-dimethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one;2-amino-5-methyl-7-(2-C,2-O-dimethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one;4-amino-7-(3-deoxy-2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-amino-7-(3-deoxy-2-C-methyl-β-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-amino-2-fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-amino-7-(3-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-amino-7-(3-C-methyl-β-D-xylofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-amino-7-(2,4-di-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;4-amino-7-(3-deoxy-3-fluoro-2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;and the corresponding 5′-triphosphates; or a pharmaceutically acceptablesalt thereof.

The compounds of the present invention may also be combined for thetreatment of HCV infection with non-nucleoside inhibitors of HCVpolymerase such as those disclosed in WO 01/77091 (18 Oct. 2001),assigned to Tularik, Inc.; WO 01/47883 (5 Jul. 2001), assigned to JapanTobacco, Inc.; WO 02/04425 (17 Jan. 2002), assigned to BoehringerIngelheim; WO 02/06246 (24 Jan. 2002), assigned to Istituto di Ricerchedi Biologia Moleculare P. Angeletti S.P.A.; WO 02/20497 (3 Mar. 2002);WO 2005/016927 (in particular JTK003), assigned to Japan Tobacco, Inc.;the content of each is incorporated herein by reference in its entirety;and HCV-796 (Viropharma Inc.).

In one embodiment, non-nucleoside HCV NS5B polymerase inhibitors thatare used in combination with the present HCV NS3 protease inhibitors areselected from the following compounds:14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylicacid;14-cyclohexyl-6-(2-morpholin-4-ylethyl)-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylicacid;14-cyclohexyl-6-[2-(dimethylamino)ethyl]-3-methoxy-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylicacid;14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylicacid; methyl({[(14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocin-11-yl)carbonyl]amino}sulfonyl)acetate;({[(14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocin-11-yl)carbonyl]amino}sulfonyl)aceticacid;14-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxamide;3-chloro-14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine11-carboxylic acid;N-(11-carboxy-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-a][1,5]benzoxazocin-7-yl)-N,N-dimethylethane-1,2-diaminiumbis(trifluoroacetate);14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylicacid;14-cyclohexyl-6-methyl-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylicacid;14-cyclohexyl-3-methoxy-6-methyl-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylicacid;14-cyclohexyl-6-[2-(dimethylamino)ethyl]-3-methoxy-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylicacid;14-cyclohexyl-6-[3-(dimethylamino)propyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylicacid;14-cyclohexyl-7-oxo-6-(2-piperidin-1-ylethyl)-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylicacid;14-cyclohexyl-6(2-morpholin-4-ylethyl)-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylicacid;14-cyclohexyl-6-[2-(diethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,I-a][2,5]benzodiazocine-11-carboxylic acid;14-cyclohexyl-6-(1-methylpiperidin-4-yl)-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylicacid;14-cyclohexyl-N-[(dimethylamino)sulfonyl]-7-oxo-6-(2-piperidin-1-ylethyl)-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxamide;14-cyclohexyl-6-[2-(dimethylamino)ethyl]-N-[(dimethylamino)sulfonyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxamide;14-cyclopentyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylicacid;14-cyclohexyl-6-[2(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylicacid;14-cyclohexyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylicacid;6-allyl-14-cyclopentyl-3-methoxy-5,6,7,8-tetrahydroindolo[2,1a][2,5benzodiazocine-11-carboxylicacid;140cyclopentyl-6-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylicacid; 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-5,6,78-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylic acid;13-cyclohexyl-5-methyl-4,5,6,7-tetrahydrofuro[3′,2′:6,7][1,4]diazocino[1,8-a]indole-10-carboxylicacid;15-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-6,7,8,9-tetrahydro-5H-indolo[2,1-a][2,6]benzodiazonine-12-carboxylicacid;15-cyclohexyl-8-oxo-6,7,8,9-tetrahydro-5H-indolo[2,1-a][2,5]benzodiazonine-12-carboxylicacid;13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylicacid; and pharmaceutically acceptable salts thereof.

The above tetracyclic indole-based HCV NS5B polymerase inhibitors may beobtained following methods A-E as outlined below, wherein differentvariables may be selected in accordance with the specific tetracyclicindole compound to be prepared:

Method A

2-Bromoindole intermediate (prepared as described in publishedInternational patent application WO2004087714) was functionalized on theindole nitrogen to introduce pre-cursor functionality W′/X′ to either orboth of the elements W/X of the tether. Pd-mediated cross-couplingmethodology (eg, Suzuki, Stille etc) then brought in the C2 aromaticbearing pre-cursor functionality Z′/Y′ to either or both of the elementsZ/Y of the tether. Functional group manipulation followed by ringclosure afforded the tetracyclic system. Ester deprotection then yieldedthe target indole carboxylic acids, with the C2 aromatic tethered to theindole nitrogen.

Following tether assembly out to the appropriate 2-haloaromatic,Pd-mediated ring closure afforded the fused tetracyclic system. Esterdeprotection then yielded the target indole carboxylic acids, with theC2 aromatic tethered to the indole nitrogen.

The C2 aromatic was introduced at the outset via Pd-mediatedcross-coupling methodology (Suzuki, Stille etc). The tether was thenbuilt up, with cyclisation onto the indole nitrogen finally closing thering. Ester deprotection then yielded the target indole carboxylicacids, with the C2 aromatic tethered to the indole nitrogen.

Fused tetracyclic intermediates arising from Methods A-C underwentmanipulation of the functionality in the tether prior to esterdeprotection to yield the target C2-tethered indole carboxylic acids.

C2-tethered indole carboxylic acids arising from Methods A-D werefurther derivatised through manipulation of the carboxylatefunctionality to give compounds bearing a carboxylate replacement orcarboxamide. During any of the above synthetic sequences it may benecessary and/or desirable to protect sensitive or reactive groups onany of the molecules concerned. This may be achieved by means ofconventional protecting groups, such as those described in ProtectiveGroups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973;and T. W. Greene & P. G. M. Wuts, Protective Groups in OrganicSynthesis, John Wiley & Sons, 3rd edition, 1999. The protecting groupsmay be removed at a convenient subsequent stage using methods known fromthe art.

The HCV NS3 protease inhibitory activity of the present compounds may betested using assays known in the art. One such assay is HCV NS3 proteasetime-resolved fluorescence (TRF) assay as described in Example 56. Otherexamples of such assays are described in e.g., International patentpublication WO2005/046712. Compounds useful as HCV NS3 proteaseinhibitors would have a Ki less than 50 μM, more preferably less than 10μM, and even more preferably less than 100 nM.

The present invention also includes processes for making compounds offormula I, II, II-a, II-b, II-c, II-d, III, III-a, III-b, III-c, orIII-d. The compounds of the present invention can be readily preparedaccording to the following reaction schemes and examples, ormodifications thereof, using readily available starting materials,reagents and conventional synthesis procedures. In these reactions, itis also possible to make use of variants which are themselves known tothose of ordinary skill in this art, but are not mentioned in greaterdetail. Furthermore, other methods for preparing compounds of theinvention will be readily apparent to the person of ordinary skill inthe art in light of the following reaction schemes and examples. Unlessotherwise indicated, all variables are as defined above. The followingreaction schemes and examples serve only to illustrate the invention andits practice. The examples are not to be construed as limitations on thescope or spirit of the invention.

General Description of Synthesis:

The compounds of the present invention may be synthesized as outlined inthe general Schemes 1 and 2.

Scheme 1 (n=0-9) outlines the synthesis of a representative molecule. Anappropriately protected 4-hydroxyproline derivative (for example, acarbamate protected nitrogen and an ester protected acid can be reactedwith carbonyldiimidazole or equivalent reagent and then reacted with anappropriately substituted isoindoline or tetrahydroisoquinoline. Thealkenyl functionality may be introduced at this or a later stage bypalladium catalyzed reaction of a halide substituent such as chloride,bromide and iodide, or other functionality such as a triflate with anorganometallic reagent such as a vinyl or allyltrialkyltin.Alternatively, the alkenyl functionality may be introduced prior to thereaction with protected prolinol.

Scheme 2 describes the synthesis of the olefin containing amino acidportion. An amino acid (either commercially available or may be preparedreadily using known methods in the art) in which the acid functionalityis protected as an ester (for example, R=methyl) can be converted toamides A by coupling an olefinic carboxylic acid utilizing a wide rangeof peptide coupling agents known to those skilled in the art such asDCC, EDC, BOP, TBTU, etc. Preparation of the sulfonamides B can beaccomplished by reaction with the appropriate sulfonyl chloride in anorganic solvent (e.g., THF) with an amine base as scavenger. Ureaderivatives C may be prepared by reacting the aminoester with a reagentsuch as carbonylduimidazole, to form an intermediate isocyanate(Catalano et al., WO 03/062192) followed by addition of a second olefincontaining amine. Alternatively, phosgene, diphosgene or triphosgene maybe used in place of carbonylduimidazole. Cyanoguanidine derivatives Dcan be prepared by reaction of the amino acid ester with diphenylC-cyanocarbonimidate in an organic solvent, followed by addition of asecond olefin containing amine. Carbamate derivatives B may be preparedby reacting an olefin containing alcohol with carbonyldiimidazole (orphosgene, triphosgene or diphosgene) in an organic solvent, followed byaddition of the amino ester.

Following functionalization of the amine, the ester can be hydrolyzedunder a range of basic conditions known to those skilled in the art(Theodora W. Greene, Protective Groups in Organic Synthesis, ThirdEdition, John Wiley and Sons, 1999).

Deprotection of the carbamate protecting group on the proline portionmay be carried out by a variety of methods known to persons skilled inthe art (Theodora W. Greene, Protective Groups in Organic Synthesis,Third Edition, John Wiley and Sons, 1999).

To complete the synthesis of the compounds of this invention, the aminoacid derivative can be coupled to the proline derivative via a widerange of peptide coupling reagents such as DCC, EDC, BOP, TBTU etc (seeScheme 1). Macrocyclization is then achieved by an olefin metathesisusing a range of catalysts that have been described in the literaturefor this purpose. At this stage the olefinic bond produced in the ringclosing metathesis may be optionally hydrogenated to give a saturatedlinkage or functionalized in alternative ways such as cyclopropanation.The proline ester is then hydrolyzed under basic conditions and coupledwith the cyclopropylamino acid ester (the appropriate alkenyl oralkylcyclopropane portion of the molecule can be prepared as describedpreviously (Llinas-Brunet et al., U.S. Pat. No. 6,323,180) and subjectedto an additional basic hydrolysis step to provide the final compounds.The proline ester can also be hydrolyzed and directly coupled to anappropriately functionalized cyclopropylamino acid acyl sulfonamide(which can be prepared according to Wang X. A. et al. WO2003/099274) toprovide the final compounds.

Olefin metathesis catalysts include the following Ruthenium basedspecies: F: Miller et al J. Am. Chem. Soc 1996, 118, 9606; G: Kingsburyet al J. Am. Chem. Soc 1999, 121, 791; H: Scholl et al Org. Lett. 1999,1, 953; Hoveyda et al US2002/0107138; K: Furstner et al. J. Org. Chem1999, 64, 8275. The utility of these catalysts in ring closingmetathesis is well known in the literature (e.g. Trnka and Grubbs, Acc.Chem. Res. 2001, 34, 18).

List of Abbreviations BOPBenzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate CH₃CN Acetonitrile DBU1,8-Diazabicyclo[5.4.0]undec-7-ene DCC Dicyclohexylcarbodiimide DCEDichloroethane DCM Dichloromethane DIPEA Diisoproylethylamine DMAP4-Dimethylamino pyridine DMF Dimethylformamide DMSO Dimethyl sulfoxideEDC N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide Et₃N TriethylamineEt₂O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol HATUO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate HBr Hydrobromic acid HCl Hydrochloric acid HOAcAcetic acid HOAt 1-Hydroxy-7-azabenzotriazole LiOH Lithium hydroxideMeOH Methanol MgSO₄ Magnesium Sulfate MTBE methyl t-butyl ether Na₂SO₄Sodium sulfate NaHCO₃ Sodium bicarbonate NaOH Sodium hydroxide NH₄ClAmmonium chloride NH₄OH Ammonium hydroxide Pd/C Palladium on carbonPd(PPh₃)₄ tetrakis(triphenylphosphine)palladium (0) PhMe Toluene PPh₃Triphenylphosphine RT room temperature TBTUO-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate THFTetrahydofuran

EXAMPLE 1 (5R,7S,10S)-10-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(III-1)

Step 1: 4-Chloroisoindoline

A mixture of 3-chlorophthalic acid anhydride (9 g, 49.2 mmol) andformamide (100 mL) was heated to 125 ° C. and stirred for 3 h. Water(300 mL) was then added and the mixture was cooled to room temperature.The mixture was filtered and the resulting white solid was washed withwater and dried to give 4-chloro-1H-isoindole-1,3(2H)-dione (7.7 g, 86%yield).

To solid 4-chloro-1H-isoindole-1,3(2H)-dione (4.0 g, 22.0 mmol) wasadded borane-THF complex (1 M/THF, 88.1 mL, 88.1 mmol) dropwise withstirring. When the addition was complete, the reaction mixture washeated to reflux (80 ° C.) and stirred for 6 h. The reaction mixture wasthen cooled to 0° C., methanol (2.8 mL, 88.1 mmol) was carefully addeddropwise and the reaction mixture was warmed to room temperature. HCl (6N) was added until the mixture was acidic and then the mixture wasconcentrated. The crude product was dissolved in 1 M HCl and extractedtwice with ethyl ether and twice with dichloromethane. The pH of theaqueous layer was adjusted to pH=11 with solid NaOH and extracted threetimes with ethyl acetate. The combined ethyl acetate extracts were driedover Na₂SO₄, filtered and concentrated to give 4-chloroisoindoline (1.8g, 53% yield). LRMS (ESI) m/z 154 [(M+H)⁺; calcd for C₈H₉ClN: 154].

Step 2: 1-tert-Butyl 2-methyl(2S,4R)-4-{[(4-chloro-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate

To a solution of N-Boc proline methyl ester (2.87 g, 11.7 mmol) in DMF(15 mL) at 0° C. was added carbonyldiimidazole (1.9 g, 11.7 mmol). Thereaction was warmed to room temperature and stirred for 30 min. Asolution of 4-chloroisoindoline (1.8 g, 11.7 mmol) in DMF (10 mL) wasthen added and the reaction mixture was heated to 50 ° C. and stirredfor 2 h. The reaction mixture was poured onto ethyl ether and 0.5 M HCland the layers were separated. The organic layer was washed with water,dried over Na₂SO₄, filtered and concentrated. The crude product waspurified on silica gel (gradient elution 10% to 90% ethyl acetate inhexanes) to give 1-tert-butyl 2-methyl(2S,4R)-4-{[(4-chloro-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate(3.3 g, 66% yield). LRMS (ESI) m/z 325 [(M+H-Boc)⁺; calcd forC₁₅H₁₈ClN₂O₄: 325].

Step 3: 1-tert-Butyl 2-methyl(2S,4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate

A solution of 1-tert-butyl 2-methyl(2S,4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate(40 mg, 0.09 mmol), vinyl tributylystannane (36 mg, 0.11 mmol) andcesium fluoride (31 mg, 0.21 mmol) in dioxane (0.5 mL) was degassed withN₂ for 15 min. Bis(tributylphospine)palladium(0) (2 mg, 0.005 mmol) wasthen added and the reaction vessel was sealed and heated to 100 ° C. for18h. After cooling, the reaction mixture was concentrated and purifed bysilica gel chromatography (10% to 90% ethyl acetate in hexanes) to give1-tert-butyl 2-methyl(2S,4R)-4-{[)4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate(10 mg, 25% yield). LRMS (ESI) m/z 317 [(M+H-Boc)⁺; calcd forC₁₇H₂₁N₂O₄: 317].

Step 4: MethylN-[(pent-4-enyloxy)carbonyl]-L-norleucyl-(4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinate

To a flask containing 1-tert-butyl 2-methyl(2S,4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate(60 mg, 0.14 mmol) was added a 4 M solution of HCl in dioxane (2 mL).After 1 h, LC-MS analysis indicated complete consumption of the startingmaterial and formation of the desired Boc product. The volatilecomponents were then removed in vacuo, and the crude material was takenup in DMF (2 mL).

To this mixture was added N-[(pent-4-en-1-yloxy)carbonyl]-L-norleucine(41 mg, 0.17 mmol) (prepared according to the procedure below), DIPEA(0.076 mL, 0.43 mmol), EDC (54 mg, 0.28 mmol) and HOAt (44 mg, 0.28mmol). After stirring at r.t. for 30 min, complete consumption of theamine was evidenced via LC-MS. The reaction mixture was then worked-upwith 0.5 N HCl and EtOAc. The organic layer was washed with brine anddried over MgSO₄. The solvent was then removed in vacuo and the crudeproduct was purified on silica (10-90% EtOAc/hexanes) to yield 60 mg(79% yield) of methyl N-[(pent-4-enyloxy)carbonyl]-L-norleucyl-(4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinate. LRMS(ESI) m/z 542 [(M+H)⁺; calcd for C₂₀H₄₀N₃O₇: 542].

Step 5: Methyl(5R,7S,10S)-10-butyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate

A solution of methylN-[(pent-4-enyloxy)carbonyl]-L-norleucyl-(4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinate(60 mg, 0.11 mmol) in DCE (20 mL) was degassed with N₂ for 15 min. TheZhan ruthenium metathesis catalyst RC-301 (Zhan Catalyst I (depicted asJ on page 43), RC-301, Zannan Pharma Ltd.) (7 mg, 0.01 mmol) was thenadded. The solution was then heated to 100 ° C. for 1 h. At this time,LC-MS and TLC analysis indicated complete consumption of the startingmaterial and formation of nearly a single product which had the desiredmass. The solvent was then removed in vacuo, and the crude product waspurified on silica (5-70% EtOAc/hexane) to yield 45 mg (79% yield) ofmethyl(5R,7S,10S)-10-butyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate.LRMS (ESI) m/z 514 [(M+H)⁺; calcd for C₂₇H₃₆N₃O₇: 514].

Step 6: (5R,7S,10S)-10-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,33:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide

To a solution of methyl(5R,7S,10S)-10-butyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate(45 mg, 0.09 mmol) in THF (2 mL), MeOH (0.5 mL), and water (1 mL) wasadded LiOH (21 mg, 0.87 mmol). The reaction mixture was heated to 40° C.and stirred for 1 h, at which time complete consumption of the methylester starting material was observed by LC-MS. The mixture was thenworked-up with 0.5 N HCl and EtOAc. The organic layer was then driedover K₂CO₃, and solvent was removed in vacuo. The crude product wastaken up in DMF (1 mL).

To the above solution was added(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride (Llinas-Brunet et al U.S. Ser. No. 03/15755 and Wang et al WO03/099274) (32 mg, 0.12 mmol), TBTU (51 mg, 0.16 mmol) and DIPEA (0.071mL, 0.40 mmol) and the reaction mixture was stirred at room temperaturefor 2 h. The reaction mixture was directly purified by reverse phaseHPLC to give(5R,7S,10S)-10-butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(27 mg, 47% yield). ¹H NMR (500 MHz, ppm, CDCl₃) δ 10.01 (s, 1 H), 7.27(m, 2 H), 7.12 (d, 1 H), 7.04 (s, 1 H), 6.40 (d, J=16.1 Hz, 1 H), 6.08(m, 1 H), 5.76 (m, 1 H), 5.44 (s, 1 H), 5.36 (d, 1 H), 5.25 (d, 1 H),5.14 (d, 1 H), 4.80-4.68 (m, 3 H), 4.59 (d, 1 H), 4.44 (m, 2 H), 4.38(m, 1 H), 4.28 (m, 1 H), 3.95 (m, 1 H), 3.77 (dd, 1 H), 2.94 (m, 1 H),2.43 (m, 2 H), 2.29 (d, 2 H), 2.06 (m, 2 H), 1.94 (m, 1 H), 1.78 (m, 4H), 1.45 (m, 1 H), 1.38-1.06 (m, 5 H), 1.04 (d, 2 H), 0.92 (t, 3 H) ppm.LRMS (ESI) m/z 712 [(M+H)⁺; calcd for C₃₅H₄₆N₅O₉S: 712].

EXAMPLE 2(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(III-2)

EXAMPLE 2 was prepared according to the procedure used for EXAMPLE 1except that 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine (preparedaccording to the procedure below) was used in place ofN-[(pent-4-en-1-yloxy)carbonyl]-L-norleucine in Step 4. ¹H NMR (500 MHz,ppm, CDCl₃) δ 9.90 (s, 1 H), 7.28 (m, 2 H), 7.13 (m, 2 H), 6.31 (d,J=15.9 Hz, 1 H), 5.74 (m, 1 H), 5.45 (m, 2 H), 5.27 (d, 1 H), 5.16 (d, 1H), 4.77-4.66 (m, 3 H), 4.55 (d, 1 H), 4.48 (t, 1 H), 4.41-4.35 (m, 2H), 4.27 (m, 1 H), 3.93 (m, 1 H), 3.74 (dd, 1 H), 2.93 (m, 1 H), 2.45(d, 2 H), 2.32 (m, 2 H), 2.10-1.95 (m, 2 H), 1.74 (m, 1 H), 1.47 (m, 1H), 1.37 (m, 2 H), 1.07 (s, 9 H) ppm. LRMS (ESI) m/z 712 [(M+H)⁺; calcdfor C₃₅H₄₆N₅O₉S: 712].

EXAMPLE 3(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl-15,15-dimethyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(III-8)

Step 1: 1-Bromo-2,3-bis(bromomethyl)benzene

A suspension of 3-bromo-o-xylene (196 g, 1.06 mol), N-bromosuccinimide(377 g, 2.15 mol) and benzoyl peroxide (0.26 g, 1.0 mmol) in carbontetrachloride (1800 mL) was heated to reflux under nitrogen for 15 h.The contents of the reaction flask were cooled, filtered, and thefiltrate evaporated. Distilled crude material under high vacuum. Majorfractions distilled between 88° C. and 152° C. Recovered 108 g purematerial. Recovered 182 g slightly crude material which could be used inthe following reaction. ¹H NMR (CDCl₃) δ (ppm) 7.56 (d, J=8.0 Hz, 1 H),7.31 (d, J=8.0 Hz, 1 H), 7.26 (s, 1 H), 7.16 (t, J=8.0 Hz, 1 H), 4.84(s, 2 H), 4.64 (s, 2 H).

Step 2: 2-Benzyl-4-bromoisoindoline

Postassium bicarbonate (204 g, 2.04 mol) was suspended in acetonitrile(12 L) and the mixture was heated to 80° C. Solutions of1-bromo-2,3-bis(bromomethyl)benzene (280 g, 0.82 mol in 500 mLacetonitrile) and benzylamine (87.5 g, 0.82 mol in 500 mL acetonitrile)were added concurrently via addition funnels over 1 h. The reactionmixture was stirred at 77° C. for 16h. The contents of the reactionflask were cooled, filtered and the solvent removed by evaporation. Thereaction was partitioned between 1M K₂CO₃ and EtOAc. The organics werewashed with brine, dried with anhydrous Na₂SO₄, filtered, andevaporated. Flash column chromatography (gradient elution: heptane to10% EtOAc in heptane) gave after evaporation the title compound as apale oil. ¹H NMR (CDCl₃) δ (ppm) 7.41-7.39 (m, 2 H), 7.37-7.34 (m, 2 H),7.32-7.27 (m, 2 H), 7.10-7.03 (m, 2 H), 4.02 (s, 2 H), (s, 2 H), 3.91(s, 2 H). LRMS (ESI) m/z 289 [(M+H)⁺; calcd for C₁₅H₁₅BrN: 289].

Converted to HCl salt in HCl/MeOH. Added MTBE and filtered solid to give118 g of product as the HCl salt.

Step 3: 2-Benzyl-4-vinylisoindoline

A solution of 2-benzyl-4-bromoisoindoline (16.7 g, 58.0 mmol) andtributyl(vinyl)tin (20.3 mL, 69.6 mmol) in toluene (400 mL) was degassedby bubbling nitrogen gas through the solution for 0.25 h.Tetrakis(triphenylphosphine)palladium (0) (1.30 g, 1.16 mmol) was addedand the resulting solution heated in a 100° C. oil bath under nitrogenfor 24 h. The contents of the reaction flask were cooled, evaporated andsubjected to flash column chromatography eluting with hexane/ethylacetate 95/5 to give after evaporation the title compound as a pale oilthat turned pink on standing. LRMS (ESI) m/z 236 [(M+H)⁺; calcd forC₁₇H₁₈N: 236].

Step 4: 4-Vinylisoindoline

A solution of 2-benzyl-4-vinylisoindoline (58 mmol) in1,2-dichloroethane (150 mL) was placed in a 1 L round bottom flask undernitrogen. To this was attached an addition funnel containing a solutionof 1-chloroethyl chloroformate (7.51 mL, 69.6 mmol) in1,2-dichloroethane. The reaction flask was cooled in an ice bath and thecontents of the addition funnel were added dropwise over 20 min keepingthe internal reaction temperature<5° C. After the addition was completethe reaction flask was allowed to warm to room temperature then heatedto reflux for 45 min. The contents of the reaction flask were cooled toroom temperature then the solvent removed by evaporation. Methanol (200mL) was added and the contents of the reaction flask were heated toreflux for 30 min. The reaction flask was cooled and the solvent removedby evaporation. Water (200 mL) was added and the resulting mixturewashed with ethyl acetate (2×250 mL). The aqueous layer was made basicwith 2N sodium hydroxide then extracted with methylene chloride (4×250mL). The combined organic extracts were dried with anhydrous sodiumsulfate, filtered and the filtrate evaporated. The remaining residue wassubjected to flash column chromatography eluting with methylenechloride/methanolammonium hydroxide 97/3/0.3 to 95/5/0.5. Evaporation offractions gave the title compound as a brown oil, 6.00g (41.4 mmol, 71%yield for two steps). LRMS (ESI) m/z 146 [(M+H)⁺; calcd for C₁₀H₁₂N:146].

Step 5: 1-tert-Butyl 2-methyl(2S,4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate

A solution of 1-tert-butyl 2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (10.1 g, 41.4 mmol) inDMF (90 mL) under nitrogen was cooled to 0° C. Solid1,1′-carbonyldiimidazole (6.70 g, 41.4 mmol) was added to the reaction.The contents of the reaction flask were warmed to room temperature andafter 2 h a solution of 4-vinylisoindoline (6.00 g, 41.4 mmol) in DMF(10 mL) was added. The reaction was heated in a 60° C. oil bath for 2 hthen cooled and poured into water and 5% potassium bisulfate. Theresulting mixture was extracted with ethyl acetate (4×250 mL). Combinedorganics were washed with brine, dried with anhydrous sodium sulfate,filtered and evaporated. Flash column chromatography eluting withhexane/ethyl acetate 70/30 gave the title compound as a white foam, 13.9g (33.4 mmol, 81% yield). LRMS (ESI) m/z 417 [(M+H)⁺; calcd forC₂₂H₂₉N₂O₆: 417]

Step 6: (3R,5S)-5-(Methoxycarbonyl)pyrrolidin-3-yl4-vinyl-1,3-dihydro-2H-isoindole-2-carboxylate Hydrochloride

A solution of 1-tert-Butyl 2-methyl(2S,4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate(13.9 g, 33.4 mmol) in ethyl acetate (700 mL) was cooled in an ice baththe saturated with hydrogen chloride gas. The reaction flask was sealedand allowed to warm to room temperature. After 3.5 h the solvent wasremoved by evaporation to give the title compound as a gray solid, 11.2g, 95% yield). ¹H NMR (500 MHz, ppm, CD₃OD) δ 7.47-7.45 (m, 1 H),7.32-7.31 (m, 1 H), 7.26-7.21 (m, 1 H), 6.79-6.73 (m, 1 H), 5.79-5.73(m, 1 H), 5.46 (s, 1 H), 5.41-5.38 (m, 1 H), 4.80-4.72 (m, 4 H), 3.91(s, 3 H), 3.74-3.63 (m, 2 H), 2.77-2.71 (m, 1 H), 2.51-2.46 (m, 1 H),LRMS (ESI) m/z 317 [(M+H)⁺; calcd for C₁₇H₂₁N₂O₄: 317].

Step 7: MethylN-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinate

To a solution of (3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl4-vinyl-1,3-dihydro-2H-isoindole-2-carboxylate hydrochloride (2.00 g,5.67 mmol) andN-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valine (1.54 g,5.67 mmol) in DMF (100 mL) was added EDC (1.41 g, 7.37 mmol), HOBt (1.00g, 7.37 mmol) and DIPEA (3.16 mL, 22.8 mmol). The reaction mixture wasstirred at RT for 18 h and then diluted with ethyl acetate and aqueousNaHCO₃. The layers were separated and the organic layer was washed withwater and brine, dried over Na₂SO₄, filtered and concentrated. The cruderesidue was purified on silica gel (gradient elution 5% to 50% ethylacetate in hexanes) to give methylN-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinate(2.75 g, 85% yield) as a white foam. LRMS (ESI) m/z 570 [(M+H)⁺; calcdfor C₃₁H₄₄N₃O₇: 570].

Step 8: Methyl(5R,7S,10S)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate

A solution of methylN-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinate(2.46 g, 4.32 mmol) in anhydrous dichloromethane (450 mL) was purgedwith nitrogen for 15 min. A solution ofbis(tricyclohexylphosphine)-3-phenyl-1H-indene-1-ylidenerutheniumdichloride (Neolyst M1 catalyst purchased from Strem) (0.40 g, 0.43mmol) in degassed, anhydrous dichloromethane (50 mL) was then addeddropwise over 30 min. The reaction mixture was stirred at RT, duringwhich time 0.2 g portions of the catalyst were added approximately every8-12 h. Reaction progress was monitored by HPLC until the reaction wascomplete at 48 h. The residue was purified by flash chromatography onsilica gel, eluting with 10-70% EtOAc/Hexane, to give methyl(5R,7S,10S)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate(1.85 g, 76% yield). LRMS (ESI) m/z 542 [(M+H)⁺; calcd for C₂₉H₄₀N₃O₇:542].

Step 9:(5R,7S,10S)-10-tert-Butyl-15,15-dimethyl-3,9,12-trioxo-1,6,7,910,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylicacid

To a solution of methyl(5R,7S,10S)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate(0.9 g, 1.67 mmol) in THF:H2O (2:1, 45 mL) was added LiOH (0.40, 16.7mmol). The reaction mixture was heated to 40° C. and stirred for 1 h.The reaction mixture was diluted with aqueous HCl, and extracted withEtOAc. The combined EtOAc layer was washed with water, brine, dried overNa₂SO₄, filtered and concentrated. The product was used with no furtherpurification. LRMS (ESI) m/z 528 [(M+H)⁺; calcd for C₂₈H₃₈N₃O₇: 528].

Step 10:(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-15,15-dimethyl-3,9,12-trioxo-1,6,7,910,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide

A solution of(5R,7S,10S)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylicacid (100 mg, 0.19 mmol),(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride (Llinas-Brunet et al U.S. Ser. No. 03/15755 and Wang et al WO03/099274) (76 mg, 0.28 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumphosphorushexafluoride (HATU, 108 mg, 0.28 mmol), DIPEA (0.073 mL, 0.42mmol) and 4-dimethylaminopyridine (2 mg) in dichloromethane (5 mL) wasstirred at 40° C. for 1 h. The reaction solution was diluted withaqueous saturated NaHCO₃, and extracted with EtOAc. The combined EtOAclayer was washed with water, brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography elutingwith 3% MeOH/CH₂Cl₂, to give(5R,7S,10S)-10-tert-butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-15,15-dimethyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(80 mg, 57% yield). ¹H NMR (400 MHz, ppm, DCl₃) δ 7.48 (s, 1 H), 7.23(s, 1 H), 7.12 (d, 1 H), 6.23 (d, J=15.9 Hz, 1 H), 5.94 (m, 1 H), 5.76(m, 1 H), 5.50 (m, 2 H), 5.43 (s, 1 H), 5.24 (d, J=16.6 Hz, 1 H), 5.11(d, 1 H), 4.70 (s, 2 H), 4.61 (d, 1 H), 4.48 (m, 3 H), 4.35 (d, 1 H),4.14 (d, 1 H), 3.74 (d, 1 H), 3.34 (d, 1 H), 2.89 (m, 1 H), 2.43 (dd, 2H), 2.06 (m, 1 H), 1.93 (m, 1 H), 1.89 (dd, 1 H), 1.43 (d, 1 H), 1.25(m, 3 H), 1.09 (s, 3 H), 1.06 (s, 9 H), 0.86 (s, 3 H). LRMS (ESI) m/z740 [(M+)⁺; calcd for C₃₇H₅₀N₅O₉S: 740].

EXAMPLE 4(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-12)

The title compound was prepared according to the procedure used forEXAMPLE 3 except that 3-methyl-N-[(hex-5-enyloxy)carbonyl]-L-valine(prepared according to the procedure below) was used in place ofN-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valine in Step 7.¹H NMR (500 MHz, ppm, CD₃OD) δ 9.13 (s, 1 H), 7.26 (t, 1 H), 7.23 (d, 1H), 7.16 (d, 1 H), 6.39 (d, J=16.4 Hz, 1 H), 6.08 (m, 1H), 5.76 (m, 1H), 5.38 (s, 1 H), 5.29 (d, 1 H), 5.12 (d, 1 H), 4.79 (d, 1 H),4.73-4.63 (m, 4 H), 4.41 (s, 1 H), 4.37 (q, 1 H), 4.24 (d, 1 H), 3.96(dd, 1 H), 3.77 (quin, 1 H), 2.94 (m, 1 H), 2.51 (q, 1 H), 2.29-2.13 (m,4 H), 1.87 (dd, 1 H), 1.68 (m, 2 H), 1.53 (quin, 2 H), 1.44 (dd, 1 H),1.25 (m, 2 H), 1.05 (s, 9 H). LRMS (ESI) m/z 726 [(M+H)⁺; calcd forC₃₆H₄₈N₅O₉S: 726].

EXAMPLE 5(5R,7S,10S)-10-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-133)

The title compound was prepared according to the procedure used forEXAMPLE 3 except that 3-methyl-N-[(hex-5-enyloxy)carbonyl]-L-norleucine(prepared according to the procedure below) was used in place ofN-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valine in Step 7.¹H NMR (500 MHz, ppm, CD₃OD) δ 7.24 (t, 1 H), 7.23 (d, 1 H), 7.15 (d, 1H), 6.91 (d, 1 H), 6.37 (d, J=16.1 Hz, 1 H), 6.07 (m, 1H), 5.75 (m, 1H), 5.39 (s, 1 H), 5.29 (d, 1 H), 5.12 (d, 1 H), 4.77 (d, 1 H), 4.66 (m,3 H), 4.57 (m, 1 H), 4.47 (q, 1 H), 4.39 (q, 1 H), 4.27 (d, 1 H), 3.90(dd, 1 H), 3.77 (quin, 1 H), 2.96 (m, 1 H), 2.49 (q, 1 H), 2.29 (m, 1H), 2.22 (m, 3 H), 1.88 (dd, 1 H), 1.75 (m, 2 H), 1.64 (m, 2 H), 1.52(m, 2 H), 1.39 (m, 5 H), 1.27 (m, 1 H), 1.18 (m, 1 H), 1.09 (m, 2 H),0.94 (t, 3 H). LRMS (ESI) m/z 726 [(M+H)⁺; calcd for C₃₆H₄₈N₅O₉S: 726].

EXAMPLE 6(5R,7S,10S)-10-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16,17,18-dodecahydro-5H-2,24:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclodocosine-7-carboxamide(III-198)

The title compound was prepared according to the procedure used forEXAMPLE 3 except that N-[(hept-6-en-1-yloxy)carbonyl]-L-norleucine(prepared according to the procedure below) was used in place ofN-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valine in Step 7.¹H NMR (500 MHz, ppm, CD₃OD) δ 9.26 (s, 1 H), 7.39 (d, 1 H), 7.24 (t, 1H), 7.15 (d, 1 H), 6.30 (d, J=15.9 Hz, 1 H), 6.20 (m, 1H), 5.75 (m, 1H), 5.53 (s, 1 H), 5.31 (d, 1 H), 5.12 (d, 1 H), 4.70 (m, 4 H), 4.43(dd, 1 H), 4.34 (m, 2 H), 4.27 (q, 1 H), 3.91 (dd, 1 H), 3.79 (quin, 1H), 3.31 (m, 1 H), 2.97 (m, 1 H), 2.31 (m, 1 H), 2.22 (m, 3 H), 1.89(dd, 1 H), 1.74 (m, 2 H), 1.66 (m, 1 H), 1.56 (m, 3 H), 1.38 (m, 8 H),1.19 (m, 1 H), 1.09 (m, 2 H), 0.94 (t, 3 H). LRMS (ESI) m/z 740 [(M+H)⁺;calcd for C₃₇H₅₀N₅O₉S: 740].

EXAMPLE 7(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-1H-5H-2,23:5,8-dimethano-4.13,2.8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-199)

The title compound was prepared according to the procedure used forEXAMPLE 3 except thatN-{[(2,2-dimethylhex-5-enyl)oxy]carbonyl}-3-methyl-L-valine (preparedaccording to the procedure below) was used in place ofN-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valine in Step 7.¹H NMR (500 MHz, ppm, CD₃OD) δ 9.17 (s, 1 H), 7.27 (t, J=7.5 Hz, 1 H),7.21 (t, J=7.5 Hz, 2 H), 7.16 (d, J=7.5 Hz, 1 H), 6.38 (d, J=16 Hz, 1H), 6.03 (m, 1 H), 5.79 (m, 1 H), 5.32 (m, 2 H), 5.13 (m, 1 H),4.82-4.77 (m, 1 H), 4.73-4.61 (m, 4 H), 4.48 (s, 1 H), 4.39 (m, 1 H),4.19 (d, J=12 Hz, 1 H), 3.96 (m, 1 H), 2.96 (m, 1 H), 2.59-2.55 (m, 1H), 2.35-2.12 (m, 4 H), 1.89 (m, 1 H), 1.49-1.23 (m, 6 H), 1.51-0.98 (m,14 H), 0.95-0.85 (m, 4 H). LRMS (ESI) m/z 754 [(M+H)⁺; calcd forC₃₈H₅₂N₅O₉S: 754].

EXAMPLE 85R,7S,10S)-10-tert-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16,17,18-dodecahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(III-200)

A solution of EXAMPLE 2 (0.32 mg, 0.45 mmol) and palladium on carbon(10% wt., 0.03 g) in EtOAc (10 mL) was vigorously stirred under ahydrogen balloon for 1 h. The reaction mixture was filtered andconcentrated. The residue was purified by reverse-phase HPLC (DeltaPak C18 column), running 40-65% CH₃CN in water (with NH₄OAc 1 g/L). Thefractions were concentrated, diluted with aqueous saturated NaHCO₃ (20mL) and extracted with CH₂Cl₂ (3×70 mL). The combined CH₂Cl₂ layers werewashed with water (50 mL), dried over Na₂SO₄, filtered and concentratedto give(5R,7S,10S)-10-tert-butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16,17,18-dodechaydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(0.31 g, 97% yield). ¹H NMR (CD₃OD, ppm) δ 7.23 (t, 1 H), 7.14 (d, 1 H),7.10 (d, 1 H), 7.02 (d, 1 H), 5.52 (s, 1H), 4.74-4.60 (m, 4 H),4.48-4.30 (m, 4 H), 3.88 (d, 1 H), 3.75 (s, 1H), 2.99 (m, 1 H), 2.62 (m,1 H), 2.41 (m, 2 H), 2.14 (m, 1 H), 1.79 (m, 1 H), 1.65-1.51 (m, 6 H),1.47-1.19 (m, 5 H), 1.07 (s, 9 H), 0.99 (t, 3 H). LRMS (ESI) m/z 716[(M+H)⁺: calcd for C₃₅H₅₀N₅O₉S: 716].

EXAMPLE 9(5R,7S,10S)-10-tert-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-201)

The title compound was prepared from EXAMPLE 4 using the proceduredescribed for EXAMPLE 8. ¹H NMR (500 MHz, ppm, CD₃OD) δ 7.23 (t, 1 H),7.14 (d, 1 H), 7.10 (d, 1 H), 7.02 (d, 1 H), 5.36 (s, 1 H), 4.71 (m, 3H), 4.64 (t, 1 H), 4.56 (m, 1 H), 4.40 (m, 2 H), 4.24 (d, 1 H), 3.96(dd, 1 H), 3.72 (quin, 1 H), 2.98 (m, 1 H), 2.58 (m, 1 H), 2.49 (m, 2H), 2.15 (t, 1 H), 1.69-1.19 (m, 15 H), 1.09 (m, 1 H), 1.06 (s, 9 H),0.98 (t, 3 H). LRMS (ESI) m/z 730 [(M+H)⁺; calcd for C₃₆H₅₂N₅O₉S: 730].

EXAMPLE 10(5R,7S,10S)-10-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-202)

The title compound was prepared from EXAMPLE 5 using the proceduredescribed for EXAMPLE 8. ¹H NMR (500 MHz, ppm, CD₃OD) δ 7.23 (t, 1 H),7.14 (d, 1 H), 7.09 (d, 1 H), 6.99 (d, 1 H), 5.39 (s, 1 H), 4.76-4.61(m, 4 H), 4.43 (m, 3 H), 4.29 (d, 1 H), 3.92 (dd, 1 H), (quin, 1 H),2.99 (m, 1 H), 2.57 (m, 1 H), 2.51 (m, 2 H), 2.19 (tt, 1 H), 1.77 (m, 1H), 1.70-1.30 (m, 20 H), 1.17 (m, 2 H), 1.10 (m, 2 H), 0.99 (t, 3 H),0.95 (t, 3 H). LRMS (ESI) m/z 730 [(M+H)⁺; calcd for C₃₆H₅₂N₅O₉S: 730].

EXAMPLE 11(5R,7S,10S)-10-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16,17,18,19,20-tetradecahydro-5H-2,24:5,8-dimethano-4,13,28,11-benzodioxatriazacyclodocosine-7-carboxamide(III-203)

The title compound was prepared from EXAMPLE 6 using the proceduredescribed for EXAMPLE 8. ¹H NMR (500 MHz, ppm, CD₃OD) δ 7.25 (t, 1 H),7.15 (d, 1 H), 7.11 (d, 1 H), 5.55 (s, 1 H), 4.70 (m, 4 H), 4.49 (m, 1H), 4.38 (t, 1 H), 4.29 (m, 2 H), 3.94 (dd, 1 H), 3.73 (quin, 1 H), 3.00(m, 1 H), 2.63 (quin, 1 H), 2.51 (m, 1 H), 2.38 (m, 1 H), 2.20 (tt, 1H), 1.76 (quin, 1 H), 1.68-1.07 (m, 24 H), 1.00 (t, 3 H), 0.95 (t, 3 H).LRMS (ESI) m/z 744 [(M+H)⁺; calcd for C₃₇H₅₄N₅O₉S: 744].

EXAMPLE 12(5R,7S,10S)-10-tert-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-15,15-dimethyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16,17,18,-dodechydro-5H-2,22:5,8-dimethano-4.13.2.8,11-benzodioxatriazacycloicosine-7-carboxamide(III-204)

The title compound was prepared from EXAMPLE 3 using the proceduredescribed for EXAMPLE 8. ¹H NMR (400 MHz, ppm, CD₃OD) δ 9.06 (s, 1 H),7.22 (dd, 1 H), 7.13 (d, 1 H), 7.07 (d, 1 H), 5.51 (s, 1 H), 4.72 (d, 2H), 4.68 (d, 2 H), 4.44 (d, 2 H), 4.28 (m, 2 H), 3.87 (dd, 1 H), 3.28(m, 1 H), 2.98 (d, 1 H), 2.85 (m, 3 H), 2.52 (m, 1 H), 2.43 (m, 2 H),2.15 (m, 1 H), 1.15-1.17 (m, 3 H), 1.41 (m, 2 H), 1.30 (m, 1 H), 1.21(m, 4 H), 1.08 (m, 1 H), 1.06 (s, 3 H), 1.05 (s, 9 H), 0.98 (t, 3 H),0.81 (s, 3 H). LRMS (ESI) m/z 744 [(M+H)⁺; calcd for C₃₇H₅₄N₅O₉S: 744].

EXAMPLE 13 (5R,7S,10S)-10-tert-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-205)

The title compound was prepared from EXAMPLE 7 using the proceduredescribed for EXAMPLE 8. ¹H NMR (500 MHz, ppm, CD₃OD) δ 9.09 (s, 1 H),7.24 (t, J=7.5 Hz, 1 H), 7.15 (d, J=7.5 Hz, 1 H), 7.10 (d, J=7.5 Hz, 1H), 5.53 (s, 1 H), 4.75-4.59 (m, 4 H), 4.44-4.37 (m, 3 H), 4.20 (d,J=12Hz, 1 H), 3.95-3.91 (m, 1 H), 3.31 (m, 2 H), 2.99-2.96 (m, 1 H),2.62-2.46 (m, 3 H), 2.17-2.13 (m, 1 H), 1.67-1.50 (m, 6 H), 1.37-1.18(m, 7 H), 1.15-0.96 (m, 16 H), 0.80 (s, 3 H), LRMS (ESI) m/z 758[(M+H)⁺; calcd for C₃₈H₅₆N₅O₉S: 758].

Alternative Preparation:

Step 1: 1-Bromo-2,3-bis(bromomethyl)benzene

To a suspension of 3-bromo-o-xylene (999 g, 5.40 mol) in chlorobenzene(9 L) at RT was added N-bromosuccinimide (1620 g, 9.1 mol) and benzoylperoxide (2.6 g, 10.8 mmol). The reaction mixture was heated to 80° C.and stirred under nitrogen for 18 h. The reaction mixture was cooled to70° C. and an additional portion of NBS (302 g, 1.7 mol) was added. Thereaction mixture was heated to 80° C. and stirred under nitrogen for 22h. The reaction mixture was cooled to RT, diluted with heptane (6 L) andfiltered. The filter cake was washed with heptane (4 L) and the combinedfiltrates were evaporated. The crude product was dissolved in heptane (2L) and chloroform (200 mL) and filtered through basic alumina (500 g).The alumina pad was washed with heptane (4 L) and the combined filtrateswere evaporated to give 1-bromo-2,3-bis(bromomethyl)benzene (1760 g,crude weight) which was used without further purification. ¹H NMR(CDCl₃) δ (ppm) 7.56 (d, J=8.0 Hz, 1 H), 7.31 (d, J=8.0 Hz, 1 H), 7.26(s, 1 H), 7.16 (t, J=8.0 Hz, 1 H), 4.84 (s, 2 H).

Step 2: 2-Benzyl-4-bromoisoindoline hydrochloride

Potassium bicarbonate (657 g, 6.56 mol) was suspended in MeCN (17 L) andthe mixture was heated to 80° C. Solutions of crude1-bromo-2,3-bis(bromomethyl)benzene (900 g, 2.63 mol in 1 L MeCN) andbenzylamine (281 g, 2.63 mol in 1 L MeCN) were added concurrently viaaddition funnels over 2 h. The reaction mixture was stirred at 77° C.for 2 h and then cooled to RT and stirred for 16 h. The contents of thereaction flask were cooled, filtered and the solvent removed byevaporation. The reaction was partitioned between water (6 L) and EtOAc(2 L). The pH was adjusted to >9 by the addition of 1M K₂CO₃, the layerswere separated and the aqueous phase extracted with an additionalportion of EtOAc (2 L). The combined organics were washed with brine,dried with anhydrous Na₂SO₄, filtered, and evaporated. The crude oil wasdiluted with EtOH (300 mL) and cooled to 0° C. Methanolic HCl was addeduntil the mixture was acidic, followed by MTBE (700 mL) and the mixturesonicated, then stirred for 15 h. MTBE (1 L) was added and the mixturewas filtered and washed with 20% EtOH in MTBE followed by MTBE. Thesolid was air dried to give 2-benzyl-4-bromoisoindoline hydrochloride(211 g). An additional portion of product (86 g) was isolated byconcentration of the mother liquors. LRMS (ESI) m/z 289 [(M+H)⁺; calcdfor C₁₅H₁₅BrN: 289].

Step 3: 4-Bromoisoindoline

To a solution of 2-benzyl-4-bromoisoindoline hydrochloride (11 g, 30.96mmol) in 200 mL EtOAc was added 1M NaOH (100 mL) and the mixture stirredfor 30 min. The organic layer was separated, washed with brine, driedover anhydrous Na₂SO₄ and solvent evaporated to an oil which wasazeotroped once with toluene (50 mL). The oil was dissolved inchlorobenzene (50 mL) and 4A molecular sieves (5 g) added to the stirredsolution. After 10 min, 1-chloroethylchloroformate (5.6 mL, 51 mmol) wasadded dropwise over 5 min. The reaction mixture was then heated to 90°C. for 2 h, cooled to room temperature and filtered. The solids werewashed with chlorobenzene (5 mL) and methanol (40 mL). The filtrate washeated to 70° C. for 1 h., allowed to cool and stirred at roomtemperature overnight. The solids were filtered, washed withchlorobenzene (2 mL) and hexane and dried to give 6.84 g of titlecompound. LRMS (ESI) m/z 198.1 [(M+H)⁺; calcd for C₈H₉BrN: 198.0].

Step 4: 1-t-Butyl 2-methyl(2S,4R)-4-1[(4-bromo-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate

To a solution of (2S,4R)-BOC-4-hydroxyproline methyl ester (126.3 g, 515mmol) in DMF (960 mL) at 0° C. was added N,N′-carbonyldiimidazole (83.51g, 515 mmol). The reaction mixture was stirred at room temperature for 3h. 4-Bromoisoindoline hydrochloride (120 g, 515 mmol) anddiisopropylethylamine (96.3 mL, 540 mmol) were added and the reactionmixture heated to 50° C. for 6 h then allowed to cool to roomtemperature and stirred overnight. The reaction mixture was partitionedbetween EtOAc (3 L) and 10% aqueous KHSO4 (6 L), the aqueousre-extracted with EtOAc (2 L) and the combined organic phases washedwith 10% aqueous NaHCO₃, brine, dried over Na₂SO₄ and solvent evaporatedto a foam (239 g). LRMS (ESI) m/z 471.0 [(M+H)⁺; calcd for C₂₀H₂₆BrN₂O₆:471.1].

Step 5: 1-t-Butyl 2-methyl(2S,4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate

To a solution of 1-t-butyl 2-methyl(2S,4R)-4-{[(4-bromo-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate(10.0 g, 21.3 mmol) in ethanol (200 mL) was added potassiumvinyltrifluoroborate (4.28 g, 32 mmol) and triethylamine (4.5 mL, 32mmol) followed by dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (175 mg, 0.21 mmol). The reactionmixture was heated to reflux for 6 h, cooled to room temperature,diluted with 10% aqueous KHSO₄ and the ethanol removed by evaporation invacuo. The aqueous residue was extracted with EtOAc and the organicphase washed with brine, dried over Na₂SO₄, solvent evaporated and crudeproduct purified by chromatography on silica eluting with 40-60%EtOAc/hexane to give, after evaporation, the title compound (8.18 g).LRMS (ESI) m/z 417.2 [(M+H)⁺; calcd for C₂₂H₂₉N₂O₆: 417.2].

Step 6: (3R,5S)-5-(Methoxycarbonyl)pyrrolidin-3-yl4-vinyl-1,3-dihydro-2H-isoindole-2-carboxylate hydrochloride

A mixture of 1-t-butyl 2-methyl(2S,4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate(18.0 g, 43.2 mmol) and HCl/dioxane (4 M) (43.2 mL, 173 mmol) wasstirred at RT for 2h. The reaction mixture was concentrated to removethe dioxane followed by concentration from Et₂O to give(3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl4-vinyl-1,3-dihydro-2H-isoindole-2-carboxylate hydrochloride as anoff-white solid (15 g) which was used without further purifcation. LRMS(ESI) m/z 317 [(M+H)⁺; calcd for C₁₇H₂₁N₂O₄: 317].

Step 7: MethylN-{[(2,2-dimethylhex-5-en-1-yl)oxylcarbonyl}-3-methyl-L-valyl-(4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2yl-)carbonyl]oxy}-L-prolinate

To a solution of (3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl4-vinyl-1,3-dihydro-2H-isoindole-2-carboxylate hydrochloride (5.0 g,14.2 mmol) andN-{[(2,2-dimethylhex-5-enyl)oxy]carbonyl}-3-methyl-L-valine (4.0 g, 14.2mmol) in DMF (20 ml) at RT was added DIPEA (2.5 mL, 14.2 mmol), EDC (5.5g, 28.4 mmol), and HOAt (1.9 g, 14.2 mmol). After 18 h the reactionmixture was poured into Et₂O, and extracted with 1 N HCl. The aqueouslayer was extracted with EtOAc, and the combined organic layers werewashed with 1 N HCl, water, NaHCO₃, and brine. The organic layer wasdried over MgSO₄ and the solvent was removed in vacuo. The crude productwas purified on silica (30% EtOAc in hexanes) to yield 4.2 g of thetitle compound as a thick oil. LRMS (ESI) m/z 584.4 [(M+H)⁺; calcd forC₃₂H₄₆N₃O₇: 584.3].

Step 8: Methyl(5R,7S,10S,18E)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxylate

To a solution of methylN-{[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinate(4.7 g, 8.05 mmol) in degassed (nitrogen bubbling for 30 min) DCM (1410mL) was added Zhan 1B catalyst (Zhan catalyst 1B, RC-303, Zannan PharmaLtd.) (0.591 g, 0.805 mmol). The mixture was then stirred at RT under anN₂ atmosphere. After 19 h, the reaction was complete and DMSO (57 μL,0.805 mmol) was added. The mixture was stirred for 2 h and the mixturewas concentrated in vacuo to ˜70 mL. The crude product was then directlypurified on silica (gradient elution, 0-50% EtOAc in hexanes) to yield4.4 g of the title compound as an oil. LRMS (ESI) m/z 556.3 [(M+H)⁺;calcd for C₃₀H₄₂N₃O₇: 556.3].

Step 9: Methyl(5R,7S,10S)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,18,11-benzodioxatriazacyclohenicosine-7-carboxylate

To a solution of methyl(5R,7S,10S,18E)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxylate(4.4 g, 7.92 mmol) in EtOAc (79 mL) was added Pd/C (0.421 g, 0.396mmol). A H₂ balloon was then placed on the reaction flask. The flask wasevacuated quickly and filled with H₂. After 17 h, the reaction wascomplete as determined by LC-MS. The Pd/C was filtered through glasswool, and the crude product was purified on silica (gradient elution,0-60% EtOAc in hexanes) to yield 4.01 g of the title compound as a whitepowder. LRMS (ESI) m/z 558.4 [(M+H)⁺; calcd for C₃₀H₄₄N₃O₇: 558.3].

Step 10:(5R,7S,10S)-10-tert-Butyl-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxylicacid

To a solution of methyl(5R,7S,10s)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxylate(5.76 g, 10.33 mmol) in THF (41.3 mL), MeOH (41.3 mL), and water (20.7mL) at RT was added LiOH (4.33 g, 103 mmol). After full conversion (45min), as judged by LC-MS, the reaction was worked up by partitioningbetween Et₂O and IN HCl. The aqueous layer was then extracted withEtOAc. The combined organic layers were dried over MgSO₄ and the solventwas removed in vacuo to yield 5.53 g of the title compound, which wasused without further purification. LRMS (ESI) m/z 544.4 [(M+H)⁺; calcdfor C₂₉H₄₂N₃O₇: 544.3].

Step 11:(5R,7S,10S)-10-tert-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropy)-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-205)

To a solution of(5R,7S,10S)-10-tert-Butyl-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxylicacid (5.53 g, 10.17 mmol) and(1R,2R)-1-amino-N-(cyclopropylsulfonyl)-2-ethylcyclopropanecarboxamidehydrochloride (3.28 g, 12.21 mmol) in DMF (50.9 mL) was added DIPEA(7.11 ml, 40.7 mmol) and HATU (5.03 g, 13.22 mmol). After fullconversion (1 h), the reaction mixture was partitioned between EtOAc and1N HCl. The organic layer was washed with brine three times, dried overMgSO₄, and the solvent was removed in vacuo. The crude material was thenpurified on silica (gradient elution, 20-80% EtOAc in hexanes) to yield5.8 g of the title compound as a white powder.

EXAMPLE 14(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16,17,18-dodecahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(III-5)

Step 1: Methyl(5R,7S,10S)-10-tert-butyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate

Methyl(5R,7S,10S)-10-tert-butyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylatewas prepared according to the procedure used for methyl(5R,7S,10S)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate(EXAMPLE 3, Step 8) except that3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine (prepared according tothe procedure below) was used in place ofN-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valine in Step 7.LRMS (ESI) m/z 514 [(M+H)⁺; calcd for C₂₇H₃₆N₃O₇: 514].

Step 2: Methyl(5R,7S,10S)-10-tert-butyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16,17,18-dodecahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate

To a solution of methyl(5R,7S,7S,10S)-10-tert-butyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16,17,18-dodecahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate(0.10 g, 0.20 mmol) in ethyl acetate (7 mL) was added 10% palladium oncarbon (0.01 g). The reaction mixture was stirred under a balloon ofhydrogen for 5 h at room temperature. Contents of the reaction flaskwere filtered through CELITE and the filtrate evaporated. The crudeproduct was used with no further purification (0.09g, 90% yield). LRMS(ESI) m/z 516 [(M+H)⁺; calcd for C₂₇H₃₈N₃O₇: 516].

Step 3:(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-1,6,7,9,10,11.12,14,15,16,17,18-dodecahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide

To a solution of methyl(5R,7S,10S)-10-tert-butyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16,17,18-dodecahydro-5H-2,22:5,8-dimethano4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate(90 mg, 0.18 mmol) in THF (2 mL) and MeOH (0.5 mL), was added LiOH (1N1.75 mL, 1.75 mmol). The reaction mixture was heated to 40° C. andstirred for 1 h, at which time complete consumption of the methyl esterstarting material was observed by LC-MS. The mixture was then worked-upwith 0.5 N HCl and EtOAc. The organic layer was then dried over K₂CO₃,and solvent was removed in vacuo. The crude product was taken up in DMF(1 mL).

To the above solution was added(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride (51 mg, 0.19 mmol), TBTU (77 mg, 0.24 mmol) and DIPEA (0.07 mL,0.40 mmol) and the reaction mixture was stirred at room temperature for2 h. The reaction mixture was directly purified by reverse phase HPLC togive(5R,7S,10S)-10-tert-butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16,17,18-dodecahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(34 mg, 28% yield). ¹H NMR (500 MHz, ppm, CD₃OD) δ 9.14 (s, 1 H), 7.23(t, 1 H), 7.13 (d, 1 H), 7.10 (d, 1 H), 5.75 (quin, 1H), 5.53 (s, 1 H),5.29 (d, 1 H), 5.12 (d, 1H), 4.75-4.59 (m, 5 H), 4.42 (m, 2 H), 4.34 (s,1 H), 4.30 (d, 1 H), 3.88 (dd, 1 H), 3.75 (m, 1 H), 3.60 (q, 2 H), 2.95(m, 1 H), 2.63 (m, 1 H), 2.41 (m, 2 H), 2.26-2.12 (m, 2H), 1.88 (dd, 1H), 1.79 (m, 1 H), 1.56 (m, 3 H), 1.41 (m, 3 H), 1.25 (m, 2 H), 1.17 (t,2 H), 1.06 (s, 9 H). LRMS (ESI) m/z 714 [(M+H)⁺; calcd for C₃₅H₁₈N₅O₉S:714].

EXAMPLE 15(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-15,15-dimethyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16,17,18-dodechaydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(III-206)

The title compound was prepared according to the procedure used forEXAMPLE 14 (using steps 2 and 3) except that methyl(5R,7S,10S)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate(EXAMPLE 3, Step 1) was used in place of methyl(5R,7S,10S)-10-tert-butyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylatein Step 2. ¹H NMR (400 MHz, ppm, CDCl₃) δ 9.91 (s, 1 H), 7.22 (t, 1 H),7.09 (d, 2 H), 7.05 (d, 1 H), 5.77 (m, 1 H), 5.60 (s, 1 H), 5.45 (d, 1H), 5.29 (s, 1 H), 5.15 (d, 1 H), 4.72 (q, 2 H), 4.40-4.55 (m, 4 H),4.30 (d, 1 H), 4.25 (d, 1 H), 3.78 (dd, 1 H), 3.26 (d, 1 H), 2.91 (m, 1H), 2.50 (m, 3 H), 2.39 (m, 3 H), 2.11 (m, 1 H), 1.98 (m, 2 H), 1.51 (m,2 H), 1.38 (m, 4 H), 1.18(m, 1 H), 1.04 (s, 9 H), 1.01 (t, 3 H), 0.79(s, 3 H). LRMS (ESI) m/z 742 [(M+H)⁺; calcd for C₃₇H₅₂N₅O₉S: 742].

EXAMPLE 16(5R,7S,10S)-10-tert-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(III-16)

To a solution of methyl(5R,7S,10S)-10-tert-butyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate(EXAMPLE 14, Step 1) (60 mg, 0.12 mmol) in THF (1 mL) and MeOH (0.5 mL)was added LiOH (1N 1.17 mL, 1.17 mmol). The reaction mixture was heatedto 40° C. and stirred for 1 h, at which time complete consumption of themethyl ester starting material was observed by LC-MS. The mixture wasthen worked-up with 0.5 N HCl and EtOAc. The organic layer was thendried over K₂CO₃, and solvent was removed in vacuo. The crude productwas taken up in DMF (1 mL).

To the above solution was added(1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropanaminiumchloride (32 mg, 0.12 mmol), TBTU (48 mg, 0.15 mmol) and DIPEA (0.044mL, 0.25 mmol) and the reaction mixture was stirred at room temperaturefor 2 h. The reaction mixture was directly purified by reverse phaseHPLC to give(5R,7S,10S)-10-tert-butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(55 mg, 67% yield). ¹H NMR (500 MHz, ppm, CD₃OD) δ 7.33 (d, 1 H), 7.26(t, 1 H), 7.16 (d, 1 H), 6.39 (d, J=15.7 Hz, 1 H), 6.13 (m, 1H), 5.37(s, 1 H), 4.69 (m, 4 H), 4.47-4.28 (m, 4 H), 3.89 (m, 1 H), 3.83 (d, 1H), 2.98 (m, 1 H), 2.40 (m, 2 H), 2.31 (m, 1 H), 2.11 (t, 1 H), 1.99 (s,1 H), 1.73 (s, 1 H), 1.60 (m, 2 H), 1.52 (m, 1 H), 1.29-1.15 (m, 3 H),1.08 (s, 9 H), 0.98 (t, 3 H). LRMS (ESI) m/z 714 [(M+H)⁺; calcd forC₃₅H,₈N₅O₉S: 714].

EXAMPLE 17(5R,7S,10S)-10-tert-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonylamino]carbonyl}-2-ethylcyclopropyl)-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-207)

Step 1: Methyl(5R,7S,10S)-10-tert-butyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxylate

Methyl(5R,7S,10S)-10-tert-butyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxylatewas prepared according to the procedure used for methyl(5R,7S,10S)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate(EXAMPLE 3, Step 8) except that3-methyl-N-[(hex-5-enyloxy)carbonyl]-L-valine (prepared according to theprocedure below) was used in place ofN-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valine in Step 7.LRMS (ESI) m/z 528 [(M+H)⁺; calcd for C₂₈H₃₈N₃O₇: 528].

Step 2:(5R,7S,10S)-10-tert-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide

EXAMPLE 17 was prepared according to the procedure used for EXAMPLE 16except using methyl(5R,7S,10S)-10-tert-butyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxylatein place ofmethyl-(5R,7S,10S)-10-tert-butyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate(EXAMPLE 14, Step 1). ¹H NMR (500 MHz, ppm, CD₃OD) δ 9.06 (s, 1 H), 7.27(t, 1 H), 7.24 (d, 1 H), 7.18 (d, 1 H), 6.40 (d, J=16.4 Hz, 1 H), 6.11(m, 1H), 5.39 (t, 1 H), 4.80 (d, 1 H), 4.69 (m, 4 H), 4.42 (s, 1 H),4.25 (d, 1 ), 3.97 (dd, 1 H), 3.79 (quin, 1 H), 2.98 (m, 1 H), 2.50 (q,1 H), 2.78 (m, 2 H), 2.15 (m, 1 H), 1.77-1.54 (m, 8 H), 1.32-1.19 (m, 4H), 1.11 (m, 1 H), 1.07 (s, 9 H), 0.98 (t, 3 H). LRMS (ESI) m/z 728[(M+H)⁺; calcd for C₃₆H₅₀N₅O₉S: 728].

EXAMPLE 18(5R,7S,10S)-10-tert-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-208)

Step 1: Methyl(5R,7S,10S)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxylate

Methyl(5R,7S,10S)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxylatewas prepared according to the procedure used for methyl(5R,7S,10S)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate(EXAMPLE 3, Step 8) except thatN-{[(2,2-dimethylhex-5-enyl)oxy]carbonyl}-3-methyl-L-valine (preparedaccording to the procedure below) was used in place ofN-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valine in Step 7.LRMS (ESI) m/z 556 [(M+H)⁺; calcd for C₃OH₄₂N₃O₇: 556].

Step 2:(5R,7S,10S)-10-tert-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide

EXAMPLE 18 was prepared according to the procedure used for EXAMPLE 16except using methyl(5R,7S,10S)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxylatein place ofmethyl-(5R,7S,10S)-10-tert-butyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate(EXAMPLE 14, Step 1). ¹H NMR (500 MHz, ppm, CD₃OD) δ 10.05 (s, 1 H),7.24 (m, 2 H), 7.17 (d, 1 H), 7.11 (d, 1 H), 6.61 (s, 1 H), 6.28 (d,J=16.4 Hz, 1 H), 5.95 (m, 1 H), 5.58 (m, 1 H), 5.31 (s, 1 H), 4.71 (m, 2H), 4.46 (d, 2 H), 4.29 (dd, 1 H), 4.17 (d, 1 H), 3.89 (d, 1 H), 3.32(d, 1 H), 2.92 (m, 1 H), 2.59 (m, 1 H), 2.21-2.30 (m, 2 H), 2.08 (m, 1H), 1.60-1.78 (m, 6 H), 1.22-1.31 (m, 5 H), 1.06 (s, 9 H), 1.04 (t, 3H), 0.093 (t, 3 H), 0.87 (s, 3 H). LRMS (ESI) m/z 756 [(M+H)⁺; calcd forC₃₈H₅₄N₅O₉S: 756].

EXAMPLE 19(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-13-methyl-3,9,12-trioxo-6,7,9,10,11,12,13,14,15,16-decahydro-1H,5H-2,22:5,8-dimethano-4,2,8,11,13-benzoxatetraazacycloicosine-7-carboxamide(III-4)

The title compound was prepared according to the procedure used forEXAMPLE 3 except that3-methyl-N-{[methyl(pent-4-enyl)amino]carbonyl}-L-valine (preparedaccording to the procedure below) was used in place ofN-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valine in Step 7.LRMS (ESI) m/z 725 [(M+H)⁺; calcd for C₃₆H₄₉N₆O₈S: 725].

EXAMPLE 20(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vincylcyclopropyl)-13-methyl-3,9.12-trioxo-1,6,7,9,10,11,12,14,15,16,17-dodecahydro-5H-2,23:5,8-dimethano-4,2,8,11,13-benzoxatetraazacyclohenicosine-7-carboxamide(III-145)

The title compound was prepared according to the procedure used forEXAMPLE 3 except that 3-methyl-N-{[methyl(hex-5-enyl)amino]carbonyl}-L-valine (prepared according to the procedure below) was used in placeof N-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valine in Step7. ¹H NMR (500 MHz, ppm, CD₃OD) δ 9.21 (s, 1 H), 7.26-7.21 (m, 2 H),7.16-7.14 (m, 1 H), 6.37 (d, J=15 Hz, 1 H), 6.13-6.09 (m, 1 H),5.83-5.77 (m, 1 H), 5.35.-5.26 (m, 3 H), 5.12-5.09 (m, 2 H), 4.72-4.58(m, 4 H), 4.40-4.36 (m, 1 H), 4.23 (d, J=12 Hz, 1 H), 4.10-4.00 (m, 1H), 3.98-3.95 (m, 1 H), 2.95-2.80 (m, 5 H), 2.51-2.47 (m, 1 H),2.28-2.13 (m, 3 H), 1.88-1.84 (m, 1 H), 1.72-1.65 (m, 1 H), 1.55-1.40(m, 4 H), 1.30-1.20 (m, 2 H), 1.15-0.98 (m, 11 H). LRMS (ESI) m/z 739[(M+H)⁺; calcd for C₃₇H₅₁N₆O₈S: 739].

EXAMPLE 21(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-14,14-dimethyl-3,9,12-trioxo-1,6,7,9,10,11,12,13,14,15,16,17-dodecahydro-5H-2,23:5,8-dimethano-4,2,8,11,13-benzoxatetraazacyclohenicosine-7-carboxamide(III-209)

The title compound was prepared according to the procedure used forEXAMPLE 3 except thatN-{[(1,1-dimethylhex-5-enyl)amino]carbonyl}-3-methyl-L-valine (preparedaccording to the procedure below) was used in place ofN-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl} -3-methyl-L-valine in Step 7.¹H NMR (500 MHz, ppm, CD₃OD) δ 7.25 (t, J=7.5 Hz, 1 H), 7.15 (t, J=8.4Hz, 2 H), 6.42 (d, J=16 Hz, 1 H), 6.01-5.98 (m, 2 H), 5.93-5.87 (m, 1H), 5.78.-5.72 (m, 1 H), 5.54-5.53 (m, 1 H), 5.26 (d, J=18 Hz, 1 H),5.10 (d, J=11 Hz, 1 H), 4.76-4.65 (m, 3 H), 4.43 (m, 1 H), 4.31-4.26 (m,2 H), 3.96-3.92 (m, 1 H), 2.93 (m, 1 H), 2.42-2.37 (m, 2 H), 2.21-2.11(m, 4 H), 1.87-1.84 (m, 1 H), 1.52-1.44 (m, 2 H), 1.42-1.39 (m, 1 H),1.36-1.28 (m, 4 H), 1.26-1.15 (m, 6 H), 1.06 (s, 9 H). LRMS (ESI) m/z753 [(M+H)⁺; calcd for C₃₈H₅₃N₆O₈S: 753].

EXAMPLE 22(6R,8S,11S)-11-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-4,10,13-trioxo-1,7,8,10,11,12,13,15,16,17-decahydro-2H,6H-3,23:6,9-dimethano-5,14,3,9,12-benzodioxatriazacyclohenicosine-8-carboxamide(III-13)

Prepared according to the procedure used for EXAMPLE 1 using5-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride in place of4-chloroisoindoline in Step 1. ¹H NMR (500 MHz, ppm, CDCl₃) δ 7.35 (d,J=8 Hz, 1 H), 7.11 (t, J=7.5 Hz, 1 H), 7.01 (br d, H=9 Hz, 1 H), 6.97(d, J=7.5 Hz, 1 H), 6.50 (d, J=15.5 Hz, 1 H), 6.03 (m, 1 H), 5.78 (m, 1H), 5.54 (br s, 1 H), 5.34 (d, J=17 Hz, 1 H), 5.14 (d, J=10 Hz, 1 H),4.95 (d, J=17 Hz, 1 H), 4.50 (dd, J=12 Hz, 6.5 Hz, 1 H), 4.29 (d, J=16Hz, 1 H), 3.90 (m, 3 H), 3.15 (m, 1 H), 2.94 (m, 1 H), 2.74 (m, 2 H),2.38-2.1 (m, 5 H), 2.00 (m, 1 H), 1.85 (m, 1 H), 1.68 (m, 1 H), 1.48 (m,1 H), 1.26 (m, 2 H), 1.08 (m, 2 H), 0.99 (s, 9 H). LRMS (ESI) m/z 726[(M+H)⁺; calcd for C₃₆H₄₈N₅O₉S: 726].

Preparation of N-[(Pent-4-eN-1-yloxy)carbonyl]-L-norleucine:

To a solution of 1-penten-4-ol (0.95 g, 11.0 mmol) in DMF (15 mL) at 0°C. was added carbonyldiimidazole (1.79 g, 11.0 mmol). The reactionmixture was warmed to room temperature and stirred for 30 min.L-norleucine methyl ester hydrochloride (2.0 g, 11.0 mmol) was thenadded, the reaction mixture was heated to 50° C. and stirred for 15 min.Upon cooling, the reaction mixture was diluted with ethyl ether andwashed twice with water. The organic layer was dried over sodiumsulfate, filtered and concentrated. The crude product was purified bysilica gel chromatography (gradient elution 10 to 90% ethyl acetate inhexanes) to afford 2.1 g (74% yield) methylN-[(pent-4-en-1-yloxy)carbonyl]-L-norleucinate as a clear oil.

To a stirred solution of methylN-[(pent-4-enyloxy)carbonyl]-L-norleucinate (8.50 g, 33.03 mmol) in THF(20 mL) was added 1N NaOH (20 mL). This reaction solution was stirred atroom temperature for 3 h, then acidified to pH 3 with 1N HCl andextracted with (3×250 mL) EtOAc. The combined EtOAc layer was washedwith 50 mL water, 50 mL brine, dried over sodium sulfate, filtered andconcentrated to give 7.09 g (88% yield) of the title product as clearoil. LRMS (ESI) m/z 244 [(M+H)⁺; calcd for C₁₂H₂₂NO₄: 244].

Preparation of 3-Methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine:

A solution of 4-pentenol (7.22 g, 83.8 mmol) and triphosgene (11.3 g,38.1 mmol) in dioxane (160 mL) was cooled to 0° C. followed by adropwise addition of DIPEA (9.85 g, 76.2 mL). The white suspension wasstirred vigorously for 1 h at 25° C., then cooled to 0° C. A 1 Nsolution of NaOH (76.2 mL) and t-butylglycine (10.0 g, 76.2 mmol) wereadded. The resulting suspension was warmed to 25° C. and stirred for 18h. Approximately half of the dioxane was removed in vacuo, the solutionwas poured into 1 N NaOH (100 nL) and washed with dichloromethane (3×150mL). The aqueous layer was acidified with 6 N HCl and the desiredproduct was extracted with dichloromethane (3×150 mL). The combinedorganics were dried over MgSO₄ and concentrated to give 13.7 g (73.9%yield) of 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine as a colorlessoil. LRMS (ESI) m/z 244 [(M+H)⁺; calcd for C₁₂H₂₂NO₄: 244].

Preparation of N-[(Hex-5-en-1-yloxy)carbonyl]-L-norleucine:

N-[(Hex-5-en-1-yloxy)carbonyl]-L-norleucine was prepared according tothe procedure for N-[(pent-4-en-1-yloxy)carbonyl]-L-norleucine by using5-hexenol instead of 4-pentenol. LRMS (ESI) m/z 258 [(M+H)⁺; calcd forC₁₃H₂₄NO₄: 258].

Preparation of 3-Methyl-N-[(hex-5-enyloxy)carbonyl]-L-valine:

3-Methyl-N-[(hex-5-enyloxy)carbonyl]-L-valine was prepared according tothe procedure for 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine byusing 5-hexenol instead of 4-pentenol. LRMS (ESI) m/z 258 [(M+H)⁺; calcdfor C₁₃H₂₄NO₄: 258].

Preparation of N-[(Hept-6-en-1-yloxy)carbonyl]-L-norleucine:

N-[(Hept-6-en-1-yloxy)carbonyl]-L-norleucine was prepared according tothe procedure for N-[(pent-4-en-1-yloxy)carbonyl]-L-norleucine by using6-heptenol instead of 4-pentenol. LRMS (ESI) m/z 272 [(M+H)⁺; calcd forC₁₄H₂₆NO₄: 272].

Preparation ofN-{[(2,2-Dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valine:

Step 1: 2,2-Dimethylpent-4-en-1-ol

A solution of 2,2-dimethyl 4-pentenoic acid (6.0 g, 46.8 mmol) inanhydrous THF was cooled in an ice bath to 0° C. A slow stream of 1Mlithium aluminum hydride in THF (56.2 mL, 56.2 mmol) was added and thereaction was allowed to warm to 25° C. The reaction mixture was stirredfor 1 h before pouring into 1N HCl and diethyl ether. The organic layerwas separated, dried over MgSO₄ and concentrated to provide2,2-dimethylpent-4-en-1-ol as a clear oil (4.7 g, 87.9% yield).

Step 2: N-{[(2,2-Dimethylpent-4-enyl)oxy]carbonyl} -3-methyl-L-valine

DIPEA (2.48 g, 19.2 mmol) was added dropwise to a 0° C. solution of2,2-dimethylpent-4-en-1-ol (2.24 g, 19.6 mmol) and triphosgene (2.56 g,8.64 mmol) in 60 mL dioxane. The resulting white suspension was stirredfor 5 min at 0° C., then allowed to warm to 25° C. over 1 h. Thesuspension was cooled to 0° C. with an ice bath, followed by addition of1 N NaOH (19.2 mL) and L-tert-butylglycine (2.52 g, 19.2 mmol). Thereaction mixture was warmed to 25° C. and stirred for 72 h. The dioxanewas removed in vacuo and the reaction mixture was basified to pH 12 with1 N NaOH. The aqueous layer was extracted with dichloromethane (3×150mL), then acidified to pH˜1 with 6 N HCl. The aqueous layer wasextracted with dichloromethane (3×150 mL). The combined organic layerswere dried over MgSO₄ and concentrated to giveN-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valine as a whitepowder (4.26 g, 827% yield). LRMS (ESI) m/z 272 [(M+H)⁺; calcd forC₁₄H₂₆NO₄:

Preparation ofN-{[(2,2-Dimethylhex-5-enyl)oxc]carbonyl}-3-methyl-L-valine:

Step 1. Ethyl 2,2-dimethylhex-5-enoate

To a stirred solution of diisopropylamine (13.38 mL, 94.70 mmol) inanhydrous THF (50 mL), at −70° C. and under nitrogen, was slowly added2.5 M n-BuLi in ether (36.50 mL, 91.25 mmol). Stirred for 15 minutes, tothis reaction solution was then added dropwise ethyl isobutyrate (11.51mL, 86.09 mmol) in THF (50 mL), stirred for 20 minutes before addeddropwise 4-bromo-1-butene (9.79 mL, 96.42 mmol) in HMPA (20 mL). Thereaction solution was then stirred to −50° C. in 5 hours, quenched with1M HCl (10 mL) and water (100 mL), then extracted with (3×125 mL) ether.The combined ether layer was washed with water (4×70 mL), aqueoussaturated NaHCO₃ (2×70 mL), dried over Na₂SO₄, filtered andconcentrated. The crude product was flash chromatographed on 120 gsilica gel 60, eluting with 1-20% EtOAc/Hexane to give the title productas clear oil (11.01 g, 75% yield). LRMS (ESI) m/z 171 [(M+H)⁺; calcd forC₁₀H₁₉O₂: 171].

Step 2: 2,2-Dimethylhex-5-en-1-ol

To a stirred solution of 1M LAH in ether (142.14 mL, 142.14 mmol), at 0°C. and under nitrogen, was added dropwise ethyl 2,2-dimethylhex-5-enoate(11.00 g, 64.61 mmol) dissolved in 100 mL anhydrous ether over 1 hour.This reaction solution was stirred at 22° C. for 20 hours, then quenchedwith water (3 mL), 1M NaOH (11 mL) and water (9 mL), dried over Na2SO₄,filtered and concentrated to give the title product (7.22 g, 87.09%). ¹HNMR (500 MHz, CDCl₃) δ 5.85-5.77 (m, 1 H); 5.01 (d, 1 H); 4.93 (d, 1 H);3.33 (d, 2 H); 2.03 (m, 2 H); 1.34 (m, 2 H); 0.89 (m, 6 H) ppm.

Step 3: N-{[(2,2-Dimethylhex-5-enyl)oxy]carbonyl} -3-methyl-L-valine

To a stirred solution of 2,2-dimethylhex-5-en-1-ol (10.75 g, 83.85 mmol)in anhydrous 1,4-dioxane (100 mL), at 0° C. and under nitrogen, wasadded triphosgene (13.69 g, 46.12 mmol) and then DIPEA (14.61 mL, 83.85mmol) cautiously. This reaction solution was stirred at 22° C. for 1hour, cooled to 0° C. and added slowly 1N NaOH (83.85 mL, 83.85 mmol)and L-tert-leucine (11.00 g, 83.85 mmol), then stirred at 22° C. for 20hours. The reaction solution was basified to pH 10 with 1N NaOH, washedwith CH₂Cl₂ (3×100 mL), acidified to pH 5 with 1N HCl and extracted withCH₂C]₂ (3×150 mL). The combined CH₂Cl₂ layer was washed with water (100mL), dried over Na2SO₄, filtered and concentrated to give the titleproduct (20.26 g, 84.66%). ¹H NMR (500 MHz, CDCl₃) δ 5.85-5.77 (m, 1 H);5.24 (d, 1 H); 5.01 (d, 1 H); 4.93 (d, 1 H); 4.20 (d, 1 H); 3.86 (d, 1H); 3.79 (d, 1 H); 2.01 (m, 2 H); 1.36 (m, 2 H); 1.04 (s, 9 H); 0.92 (m,6 H) ppm. LRMS (ESI) m/z 286 [(M+H)⁺; calcd for C₁₅H₂₈NO₄: 286].

Preparation of 3-Methyl-N-{[methyl(pent-4-enyl)amino]carbonyl}-L-valine:

Step 1: N-Methylpent-4-enamide

A solution of DIPEA (14.7 mL, 84.7 mmol) in methylenechloride (400 mL)was cooled using an ice bath then saturated with methylamine gas. Asolution of 4-pentenoyl chloride (10.0 g, 84.7 mmol) inmethylenechloride (100 mL) was added to the reaction flask dropwise viaan addition funnel. Contents of the reaction flask were stirred withcooling 2 h then washed with 5% potassium bisulfate. The organic layerwas dried with sodium sulfate (anh.), filtered and evaporated. Flashcolumn chromatography eluting with ethyl acetate/hexane 60/40 gave afterevaporation N-methylpent-4-enamide as a colorless oil, 8.65 g (90%yield).

Step 2: N-Methylpent-4-en-1-amine

A solution of N-methylpent-4-enamide (8.20 g, 72.3 mmol) intetrahydrofuran (200 mL) was cooled to −70° C. under nitrogen. Lithiumaluminum hydride solution (1.0 M in ether, 200 mL, 200 mmol) was addedin a stream. Contents of the reaction flask were first warmed to 0° C.and placed in a freezer for 18 h then heated to 50° C. for 5 h. Thereaction was cooled to −70° C. and quenched by dropwise addition ofwater (8 mL), 2N sodium hydroxide (8 mL), then water (10 mL). Contentsof the reaction flask were warmed to room temperature, filtered, and thefiltrate dried with anhydrous magnesium sulfate. Filtration andconcentration afforded the N-methylpent-4-en-1-amine as a colorless oil,3.16 g (44% yield).

Step 3: Methyl 3-methyl-N-(oxomethylene)-L-valinate

A solution of methyl 3-methyl-L-valinate hydrochloride (10.0 g, 54.9mmol) and pyridine (22.3 mL, 276 mmol) in methylenechloride (300 mL) wascooled in an ice bath under nitrogen. Phosgene (20% in toluene, 41.1 mL,83.0 mmol) was added dropwise over 0.5 h using an addition funnel. Theresulting mixture was stirred 1 h then poured into cold 1M hydrochloricacid and extracted with methylenechloride (3×100 mL). The combinedorganic extracts were washed with brine, dried with anhydrous magnesiumsulfate, filtered and concentrated. Flash column chromatography elutingwith hexane/ethyl acetate 90/10 gave methyl3-methyl-N-(oxomethylene)-L-valinate as an orange oil, 6.99 g (74%yield).

Step 4: Methyl3-methyl-N-{[methyl(pent-4-enyl)amino]carbonyl}-L-valinate

A solution of N-methylpent-4-en-l-amine (2.0 g, 20.2 mmol) intetrahydrofuran (20 mL) was stirred at room temperature under nitrogen.To this was added methyl 3-methyl-N-(oxomethylene)-L-valinate (3.5 g,20.2 mmol) and the resulting solution stirred 2 h. Contents of thereaction flask were evaporated and subjected to flash columnchromatography eluting with hexane/ethyl acetate 60/40 to give methyl3-Methyl-N-{[methyl(pent-4-enyl)amino]carbonyl}-L-valinate as an orangeoil, 3.02 g (55% yield).

Step 5: 3-Methyl-N-{[methyl(pent-4-enyl)amino]carbonyl}-L-valine

A solution of methyl3-methyl-N-{[methyl)pent-4-enyl)amino]carbonyl}-L-valinate (3.00 g, 11.2mmol), lithium hydroxide (1M, 56.0 mL, 56.0 mmol) in tetrahydrofuran (40mL) was heated to 50 ° C. for 1 h. Contents of the reaction flask werecooled and evaporated to remove tetrahydrofuran. The remaining mixturewas poured into 5% potassium bisulfate and extracted with methylenechloride (3×100 mL). The combined organic extracts were dried withanhydrous sodium sulfate, filtered and evaporated to give the titlecompound as a colorless oil, 2.87 g (100% yield). LRMS (ESI) mn/z 257[(M+H)⁺; calcd for C₁₃H₂₅N₂O₃: 257].

Preparation of 3-Methyl-N-{[methyl(hex-5-enyl)amino]carbonyl}-L-valine:

Step 1: 5-Hexenoyl chloride

A solution of hex-5-enoic acid (10.0 g, 87.7 mmol) in methylenechloride(250 mL) was cooled in an ice bath under nitrogen. To this was addedoxalyl chloride (9.40 mL, 105 mmol) followed by DMF (0.5 mL). Thereaction was warmed to room temperature and stirred 18h. Solvent wasremoved by evaporation to afford the title compound as a colorless oil.

3-Methyl-N-{[methyl(hex-5-enyl)amino]carbonyl}-L-valine

3-Methyl-N-{[methyl(hex-5-enyl)amino]carbonyl}-L-valine was preparedaccording to the procedure for3-methyl-N-{[methyl(pent-4-enyl)amino]carbonyl}-L-valine (Steps 1-5) byusing 5-hexenoyl chloride instead of 4-pentenoyl chloride in Step 1.LRMS (ESI) m/z 271 [(M+H)⁺; calcd for C₁₄H₂₇N₂O₃: 271].

Preparation ofN-{[(1,1-Dimethylhex-5-enyl)amino]carbonyl}-3-methyl-L-valine:

Step 1: 2-Methylhept-6-en-2-amine

Cerium chloride (25.0 g, 102 mmol) was dried in a 1 L round bottom flaskunder vacuum for 24 h at 125° C. The flask was cooled to roomtemperature and tetrahydrofuran (200 mL) was added and the resultingmixture stirred 24 h. The reaction flask was cooled to -70° C. andmethyl lithium (1.6M, 100 mL, 160 mmol) was added via cannula. Thereaction was stirred 0.5 h with cooling then warmed to 25° C. over 20min. The reaction was cooled to −70° C. and hex-5-enenitrile (5.0 mL,44.1 mmol) in tetrahydrofuran (5 mL) was added to give a red-orangesuspension. After stirring 20 min the reaction was quenched by slowaddition of ammonium hydroxide (10 mL) and warmed to room temperature.The reaction was filtered through CELITE and the filtrate concentrated.Flash column chromatography methylenechloride/methanol/ammoniumhydroxide 90/10/1 gave after evaporation of fractions the title compoundas a colorless oil, 1.15 g (21% yield). LRMS (ESI) m/z 285 [(M+H)⁺;calcd for C₁₅H₂₉N₂O₃: 285].

N-{[(1,1-Dimethylhex-5-enyl)amino]carbonyl}-3-methyl-L-valine

N-{[(1,1-Dimethylhex-5-enyl)amino]carbonyl}-3-methyl-L-valine wasprepared according to the procedure from3-methyl-N-{[methyl)pent-4-enyl)amino]carbonyl}-L-valine (Steps 4-5) byusing 2-methylhept-6-en-2-amine instead of N-methylpent-4-en-1-amine inStep 4.

Preparation of(1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropanaminiumchloride:

A mixture of(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride (Llinas-Brunet et al U.S. Ser. No. 03/15755 and Wang et al WO03/099274) (0.05 g, 0.187 mmol) and palladium on carbon (10% wt., 0.01g)in EtOAc (5 mL) was vigorously stirred under hydrogen atmosphereprovided by a hydrogen balloon for 1 hour. The reaction mixture wasfiltered and concentrated to give(1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropanaminiumchloride (0.045 g, 89% yield).

EXAMPLE 23(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-210)

EXAMPLE 23 was prepared from(5R,7S,10S)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxylicacid (EXAMPLE 13 Alternative Preparation, Step 10) using the procedurefor EXAMPLE 3, Step 10. ¹H NMR (500 MHz, CD₃OD, ppm) δ 7.25-7.09 (m, 3H), 5.82-5.74 (m, 1 H), 5.35-5.29 (m, 2 H), 5.15-5.12 (m, 1 H),4.75-4.59 (m, 3 H), 4.45-4.38 (m, 2 H), 4.21-4.12 (m, 1 H), 4.13-4.09(m, 1 H), 3.95-3.92 (m, 1 H), 2.98-2.94 (m, 1 H), 2.62-2.54 (m, 1 H),2.49-2.46 (m, 2 H), 2.25-2.21 (m, 1 H), 2.19-2.13 (m, 1 H), 1.90-1.88(m, 1 H), 1.52 (m, 2 H), 1.48-1.45 (m, 1 H), 1.40-1.18 (m, 6 H),1.15-1.00 (m, 14 H), and 0.81 (m, 4 H). LRMS (ESI) m/z 756.4 [(M+H)³⁰ ;calcd for C₃₈H₅₃N₅O₉S: 755.9].

EXAMPLE 24(5′R,7′S,10′S,18′E)-10′-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinycyclopropyl)-3′,9′,12′-trioxo-6′,7′,9′,10′,11′,12′,16′,17′-octahydro-1′H,5′H-spiro]cyclohexane-1,15═-[4,13]dioxa[2,8,11]triaza[2,23:5,8]dimethano[4,13,2,8,11]benzodioxatriazacyclohenicosine]-7′-carboxamide(III-211)

EXAMPLE 24 was prepared using the procedures from EXAMPLE 13 AlternatePreparation, Steps 7, 8, 10 and 11 usingN-{[(1-but-3-en-1-ylcyclohexyl)methoxy]carbonyl}-3-methyl-L-valine inStep 7 and(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. ¹H NMR (500 MHz, CD₃OD, ppm) δ 7.27 (t, J=7.6 Hz, 1H), 7.17 (m, 2 H), 7.08 (d, J=9.8 Hz, 1 H), 6.42 (d, J=16.4 Hz, 1 H),5.95-5.89 (m, 1 H), 5.83-5.75 (m, 1 H), 5.33-5.28 (m, 1 H), 5.13 (d,J=10.3 Hz, 1 H), 4.83 (d, J=16.6 Hz, 1 H), 4.73-4.65 (m, 3 H), 4.61 (d,J=11.2 Hz, 1 H), 4.49 (d, J=9.8 Hz, 1 H), 4.41-4.38 (m, 1 H), 4.23 (d,J=11.0 Hz, 1 H), 3.94 (dd, J=12.0 & 3.4 Hz, 1 H), 3.62 (d, J=11.0 Hz, 1H), 2.98-2.93 (m, 1 H), 2.62 (q, J=6.6 Hz, 1 H), 2.31-2.02 (m, 4 H),1.88 (m, 1 H), 1.59-1.41 (m, 10 H), 1.31-1.19 (m, 4 H), and 1.12-1.06(m, 10 H). LRMS (ESI) m/z 794.6 [(M+H)⁺; calcd for C₄₁H₅₆N₅O₉S: 794.4].

EXAMPLE 25(5′R,7′S,10′S)-10′-tert-Butyl]-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl-3′,9′,12′-trioxo-6′,7′,9′,10′,11′,12′,16′,17′,18′,19′-decahydro-1′H,5′H-spiro[cyclohexane-1,15′-[4,13]dioxa[2,8,11]triaza[2,23:5,8]dimethano[4,13,2,8,11]benzodioxatriazacyclohenicosine]-7′-carboxamide(III-212)

EXAMPLE 25 was prepared from EXAMPLE 24 using the procedure describedfor EXAMPLE 8. ¹H NMR (500 MHz, CD₃OD, ppm) δ 7.22 (t, J=7.4 Hz, 1 H),7.14 (d, J=7.6 Hz, 1 H), 7.08 (d, J=8.1 Hz, 1 H), 5.34 (s, 1 H),4.74-4.57 (m, 4 H), 4.43 (m, 2 H), 4.26-4.18 (m, 2H), 3.90 (d, J=9.3 Hz,1 H), 3.53 (d, J=10.8 Hz, 1 H), 2.98 (m, 1 H), 2.62-2.46 (m, 3 H), 2.13(m, 1 H), and 1.68-0.92 (m, 39 H). LRMS (ESI) m/z 798.6 [(M+H)⁺; calcdfor C₄₁H₆₀N₅O₉S: 798.4].

EXAMPLE 26(5′R,7′S,10′S,18′E)-10′-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3′,9′,12′-trioxo-6′,7′,9′,10′,11′,12′,16′,17′-octahydro-1′H,5′H-spiro[cyclopentane-1,15′-[4,13]dioxa[2,8,11]triaza[2,23:5,8]dimethano[4,13,2,8,1]benzodioxatriazacyclohenicosine]-7′-carboxamide(III-213)

EXAMPLE 26 was prepared using the procedures from EXAMPLE 13 AlternatePreparation, Steps 7, 8, 10 and 11 usingN-{[(1-but-3-en-1-ylcyclopentyl)methoxy]carbonyl}-3-methyl-L-valine inStep 7 and(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminumchloride in Step 11. ¹H NMR (500 MHz, CD₃OD, ppm) δ 7.27 (t, J=7.6 Hz, 1H), 7.20 (d, J=7.6 Hz, 1 H), 7.17 (d, J=7.6 Hz, 1 H), 7.06 (d, J=9.8 Hz,1 H), 6.41 (d, J=16.1 Hz, 1 ), 6.02-5.96 (m, 1 H), 5.82-5.75 (m, 1 H),5.31 (m, 2 H), 5.13 (d, J=10.3 Hz, 1 H), 4.82 (d, J=14.9 Hz, 1 H),4.73-4.65 (m, 4 H), 4.48 (d, J=9.8 Hz, 1 H), 4.41-4.38 (m, 1 H), 4.22(d, J=11.2 Hz, 1 H), 3.95 (dd, J=12.0 & 3.4 Hz, 1 H), 3.45 (d, J=11.0Hz, 1 H), 2.96 (m, 1 H), 2.60 (q, J=6.8 Hz, 1 H), 2.33 (m, 4 H), 2.55(q, J=9.0 Hz, 1 H), 2.17 (m, 2 H), 1.90-1.83 (m, 2 H), 1.68 (m, 4 H),1.60-1.41 (m, 4 H), 1.28 (m, 3 H), and 1.13-1.06 (m, 10 H). LRMS (ESI)m/z 780.4 [(M+H)^('); calcd for C₄₀H₅₄N₅O₉S: 780.4].

EXAMPLE 27(5′R,7′S,10′S)-10′-tert-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-3′,9′,12′-trioxo-6′,7′,9′,10′,12′,16′,17′,18′,19′-decahydro-1′H,5′H-spiro[cyclopentane-1,15′-[4,13]dioxa[2,8,11]triaza[2,23:5,8]dimethano[4,13,2,8,11]benzodioxatriazacyclohenicosine]-7′-carboxamide(III-214)

EXAMPLE 27 was prepared from EXAMPLE 26 using the procedure describedfor EXAMPLE 8. ¹H NMR (500 MHz, CD₃OD, ppm) δ 9.08 (s, 1 H), 7.23 (t,J=7.3 Hz, 1 H), 7.15 (d, J=7.3 Hz, 1 H), 7.09 (d, J=7.1 Hz, 1 H), 5.36(s, 1 H), 4.75-4.58 (m, 4 H), 4.43 (m, 2 H), 4.34 (d, J=10.5 Hz, 1 H),4.21 (d, J=11.7 Hz, 1 H), 3.91 (d, J=10.0 Hz, 1 H), 2.98 (brs, 1 H),2.59-2.49 (m, 3 H), 2.14 (m, 1 H), 1.82 (m, 1 H), and 1.62-0.94 (m, 34H). LRMS (ESI) m/z 784.5 [(M+H)⁺; calcd for C₄₀H₅₈N₅O₉S: 784.4].

EXAMPLE 28(5′R,7′S,10′S,18′E)-10′-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3′,9′,12′-trioxo-6′,7′,9′,10′,11′,12′,16′,17′-octahydro-1′H5′H-spiro[cyclobutane-1,15′-[4,13]dioxa[2,8,11]triaza[2,23:5,8]dimethano[4,13,2,8,11]benzodioxatriazacyclohenicosine]-7′-carboxamide(III-215)

EXAMPLE 28 was prepared using the procedures from EXAMPLE 13 AlternatePreparation, Steps 7, 8, 10 and 11 usingN-{[(1-but-3-en-1-ylcyclobutyl)methoxy]carbonyl}-3-methyl-L-valine inStep 7 and(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. ¹H NMR (500 MHz, CD₃OD, ppm) δ 7.25 (t, J=7.6 Hz, 1H), 7.20 (d, J=7.6 Hz, 1 H), 7.16 (d, J=7.6 Hz, 1 H), 7.02 (d, J=9.3 Hz,1 H), 6.40 (d, J=16.1 Hz, 1 H), 6.04-5.98 (m, 1 H), 5.81-5.73 (m, 1 H),5.31 (m, 2 H), 5.11 (d, J=11.5 Hz, 1 H), 4.80 (m, 1 H), 4.72-4.62 (m,4H), 4.43 (d, J=9.5 Hz, 1 H), 4.40-4.36 (m, 1 H), 4.22 (d, J=11.5 Hz, 1H), 3.93 (dd, J=12.0 & 3.7 Hz, 1 H), 3.78 (d, J=11.0 Hz, 1 H), 2.93(sep, J=4.2 Hz, 1 H), 2.58 (q, J=7.4 Hz, 1 H), 2.32 (m, 1 H), 2.23-2.11(m, 4H), 1.98-1.84 (m, 5 H), 1.73 (m, 1 H), 1.55 (m, 2 H), 1.44 (m, 1H), 1.24 (m, 2 H), and 1.06 (s, 9 H), LRMS (ESI) m/z 766.4 [(M+H)⁺;calcd for C₃₉H₅₂N₅O₉S: 766.3].

EXAMPLE 29(5′R,7′S,10′S)-10′-tert-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbony}-2-ethylcyclopropyl)-3′,9′,12′-trioxo-6′,7′,9′,10′,11′,12′,16′,17′,18′,19′-dechaydro-1′H,5′H-spiro[cyclobutane-1,15′-[4,13]dioxa]2,8,11]triaza[2,23:5,8]dimethano[4,13,2,8,11]benzodioxatriazacyclohenicosine]-7′-carboxamide(III-216)

EXAMPLE 29 was prepared from EXAMPLE 28 using the procedure describedfor EXAMPLE 8. ¹H NMR (500 MHz, CD₃OD, ppm) δ 7.21 (t, J=7.5 Hz, 1 H),7.13 (d, J=7.3 Hz, 1 H), 7.07 (d, J=7.1 Hz, 1 H), 7.06 (d, J=10.3 Hz, 1H), 5.35 (m, 1 H), 4.71 (m, 1 H), 4.66-4.57 (m, 3 H), 4.44-4.33 (m, 3H), 4.21 (d, J=11.0 Hz, 1 H), 3.89 (dd, J=11.7 & 3.2 Hz, 1 H), 3.68 (d,J=10.7 Hz, 1 H), 2.96 (sep, J=4.3 Hz, 1 H), 2.54 (m, 3 H), 2.13 (m, 1H), 2.04 (m, 1 H), 1.85 (m, 2 H), 1.76 (q, J=8.8 Hz, 2 H), 1.65-1.39 (m,9 H), 1.32-1.16 (m, 5 H), and 1.12-0.87 (m, 14 H). LRMS (ESI) m/z 770.6[(M+H)⁺; calcd for C₃₉H₅₆N₅O₉S: 770.4].

EXAMPLE 30(5′R,7′S,10′S,18′E)-10′-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3′,9′,12′-trioxo-6′,7′,9′,10′,11′,12′,16′,17′-octahydro-1′H,5′-spiro[cyclopropane-1,15′-[4,13]dioxa[2,8,11]triaza[2,23:5,8]dimethano[4,13,2,8,11benzodioxatriazacyclohenicosine]-7′-carboxamide(III-217)

EXAMPLE 30 was prepared using the procedures from EXAMPLE 13 AlternatePreparation, Steps 7, 8, 10 and 11 usingN-{[(1-but-3-en-1-ylcyclopropyl)methoxy]carbonyl}-3-methyl-L-valine inStep 7 and(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. ¹H NMR (500 MHz, CD₃OD, ppm) δ 7.25 (t, J=7.6 Hz, 1H), 7.17 (d, J=6.6 Hz, 1 H), 7.15 (d, J=6.8 Hz, 1 H), 7.04 (d, J=8.8 Hz,1 H), 6.41 (d, J=16.1 Hz, 1 H), 6.02 (m, 1 H), 5.77 (m, 1 H), 5.34 (m, 1H), 5.29 (d, J=17.1 Hz, 1 H), 5.11 (d, J=11.2 Hz, 1 H), 4.87 (m, 1 H),4.67 (m, 3 H), 4.42 (m, 2 H), 4.24 (d, J=11.0 Hz, 1 H), 3.94 (dd, J=11.7& 3.7 Hz, 1 H), 3.01 (d, J=11.7 Hz, 1 H), 2.94 (sep, J=4.2 Hz, 1 H),2.58 (q, J=5.3 Hz, 1 H), 2.40 (m, 1 H), 2.18 (m, 3 H), 1.87 (m, 2 H),1.43 (m, 1 H), 1.24 (m, 2 H), 1.05 (m, 11 H), 0.58 (m, 1 H), and 0.44(m, 3 H). LRMS (ESI) m/z 752.3 [(M+H)⁺; calcd for C₃₈H₅₀N₅O₉S: 752.3].

EXAMPLE 31(5′R,7′S,10′S)-10′-tert-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-3′,9′,12′-trioxo-6′,7′,9′,10′,11′,12′,16′,17′,18′,19′-decahydro-1′H,5′H-spiro[cyclopropane-1,15′-[4,13]dioxa[2,8,11]triaza[2,23:5,8]dimethano[4,13,2,8,11benzodioxatriazacyclohenicosine]-7′-carboxamide(III-218)

EXAMPLE 31 was prepared from EXAMPLE 30 using the procedure describedfor EXAMPLE 8. ¹H NMR (500 MHz, CD₃OD, ppm) δ 7.21 (t, J=7.5 Hz, 1 H),7.14 (d, J=7.6 Hz, 1 H), 7.06 (d, J=7.6 Hz, 1 H), 7.05 (d, J=9.8 Hz, 1H), 5.36 (m, 1 H), 4.86 (m, 1 H), 4.75-4.59 (m, 4 H), 4.45 (m, 1 H),4.36 (d, J=9.5 Hz, 1 H), 4.22 (d, J=11.2 Hz, 1 H), 3.90 (dd, J=12.0 &3.4 Hz, 1 H), 2.97 (sep, J=4.0 Hz, 1 H), 2.86 (d, J=11.5 Hz, 1 H), 2.54(m, 3 H), 2.14 (m, 1 H), 1.74 (m, 1 H), 1.64-1.52 (m, 6 H), 1.45-1.19(m, 6 H), 1.11-0.89 (m, 14 H), 0.55 (m, 1 H), 0.36 (m, 1 H), and 0.30(m, 2 H). LRMS (ESI) m/z 756.3 [(M+H)⁺; calcd for C₃₈H₅₄N₅O₉S: 756.4].

EXAMPLE 32(5R,7S10S,17E)-N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-10-(1-methylcyclohexyl)-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(III-219)

EXAMPLE 32 was prepared using the procedures from EXAMPLE 13 AlternatePreparation, Steps 7, 8, 10 and 11 using(2S)-(1-methylcyclohexyl){[(pent-4-en-1-yloxy)carbonyl]amino}acetic acidin Step 7 and(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. ¹H NMR (500 MHz, CD₃OD, ppm) δ 7.32 (d, J=7.5 Hz,1H), 7.25 (t, J=8.0 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 7.15 (d, J=9.5 Hz,1H), 6.37 (d, J=16.0 Hz, 1H), 6.10 (m, 1H), 5.72 (m, 1H), 5.37 (s, 1H),5.28 (dd, J=17.0 and 1.5 Hz, 1H), 5.12 (dd, J=10.0 and 1.5 Hz, 1H), 4.67(m, 4H), 4.42 (m, 3H), 4.28 (m, 1H), 3.87 (m, 2H), 2.93 (m, 1H), 2.40(m, 2H), 2.31 (m, 1H), 2.22 (m, 1H), 2.12 (m, 1H), 2.0 (m, 1H), 1.88(dd, J=8.25 and 5.5 Hz, 1H), 1.71 (m, 1H), 1.63-1.36 (m, 10H), 1.30-1.19(m, 4H), 1.09 (s, 3H), and 1.08 (m, 2H). LRMS (ESI) m/z 752.3 [(M+H)⁺;calcd for C₃₈H₅₀N₅O₉S: 752.3].

EXAMPLE 33(5R,7S,10S)—N-((1R,2R)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-10-(1-methylcyclohexyl)-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16,17,18-dodecahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(III-220)

EXAMPLE 33 was prepared from EXAMPLE 32 using the procedure describedfor EXAMPLE 8. ¹H NMR (500 MHz, CD₃OD, ppm) δ 7.23 (t, J=7.5 Hz, 1H),7.13 (d, J=7.5 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 7.04 (d, J=9.5 Hz, 1H),5.52 (t, J=3.0 Hz, 1H), 4.67 (m, 4H), 4.45-4.29 (m, 4H), 3.90 (dd,J=12.0 and 3.0 Hz, 1H), 3.74 (m, 1H), 2.96 (m, 1H), 2.62 (m, 1H). 2.44(m, 1H), 2.40 (m, 1H), 2.15 9m, 1H), 1.87 (m, 1H), 1.64-1.15 (m, 24H),1.07 (m, 2H), 1.06 (s, 3H), and 0.97 (t, J=7.5 Hz, 1H). LRMS (ESI) m/z756.4 [(M+H)⁺; calcd for C₃₈H₅₄N₅O₉S: 756.4].

EXAMPLE 34(5R,7S,10S,18E)-N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-15,15-dimethyl-10-(1-methylcyclohexyl)-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-221)

EXAMPLE 34 was prepared using the procedures from EXAMPLE 13 AlternatePreparation, Steps 7, 8, 10 and 11 using(2S)-({[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}amino)(1-methylcyclohexyl)aceticacid in Step 7 and(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. ¹H NMR (400 MHz, CDCl₃, ppm) δ 10.11 (s, 1 H), 7.23(t, J=9.7 Hz, 1 H), 7.16 (d, J=7.3 Hz, 1 H), 7.10 (d, J=7.4 Hz, 1 H),6.69(s, 1 H), 6.28 (d, J=16.1 Hz, 1 H), 5.93 (m, 1 H), 5.86-5.77 (m, 1H), 5.54 (d, J=9.6 Hz, 1 H), 5.33 (s, 1 H), 5.23 (d, J=17.2 Hz, 1 H),5.13 (d, J=11.4 Hz, 1 H), 4.77-4.62 (m, 3 H), 4.69-4.52 (m, 2 H), 4.42(d, J=9.8 Hz, 1 H), 4.29 (dd, J=10.6, 6.7 Hz, 1 H), 4.12 (m, 1 H), 3.91(dd, J=11.6, 3.8 Hz, 1 H), 3.48 (q, J=7.0 Hz, 1 H), 3.31 (d, J=10.8 Hz,1 H), 2.88 (m, 1 H), 2.62-2.57 (m, 1 H), 2.38-2.17 (m, 2 H), 2.17-1.97(m, 3 H), 1.63-1.52 (m, 4 H), 1.52-1.26 (m, 9 H), 1.22-1.11 (m, 3 H),1.05 (s, 3 H), 0.99 (s, 3 H), and 0.86 (s, 3 H). LRMS (ESI) m/z 794.4[(M+H)⁺; calcd for C₄₁H₅₆N₅O₉S: 795.0].

EXAMPLE 35(5R,7S,10S)—N-((1R,2R)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-15,15-dimethyl-10-(1-methylcyclohexyl)-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-222)

EXAMPLE 35 was prepared from EXAMPLE 34 using the procedure describedfor EXAMPLE 8. ¹H NMR (400 MHz, CDCl₃, ppm) δ 9.97 (s, 1 H), 7.22 (m, 1H), 7.09 (d , J=7.5 Hz, 1 H), 7.06 (d, J=7.3 Hz, 1 H), 6.70 (s, 1 H),5.52 (d, J=9.7 Hz, 1 H), 5.34 (m, 1 H), 4.72 (m, 2 H), 4.51-4.38 (m, 3H), 4.31 (m, 1 H), 4.18 (d, J=12.0 Hz, 1 H), 3.87 (dd, J=11.8, 3.4 Hz, 1H), 3.48 (q, J=7.0 Hz, 2 H), 3.25 (d, J=10.7 Hz, 1 H), 2.93 (m, 1 H),2.63-2.50 (m, 2 H), 2.47-2.28 (m, 2 H), 1.64-1.33 (m, 13 H), 1.32-1.14(m, 3 H), 1.11-1.08 (m, 11 H), 1.06 (s, 3 H), 0.96 (s, 3 H), and 0.79(s, 3 H). LRMS (ESI) m/z 798.6 [(M+H)⁺; calcd for C₄₁H₆₀N₅O₉S: 799.0].

EXAMPLE 36(5R,7S,10S,18E)-N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-10-(2,2,2-trifluoroethyl)-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-134)

EXAMPLE 36 was prepared using the procedures from EXAMPLE 13 AlternatePreparation, Steps 7, 8, 10 and 11 using(2S)-4,4,4-trifluoro-2-{[(hex-5-en-1-yloxy)carbonyl]amino}butanoic acidin Step 7 and(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. LRMS (ESI) m/z 752.3 [(M+H)⁺; calcd forC₃₄H₄₀N₅O₉S: 752.3].

EXAMPLE 37(5R,7S,10S,18E)-10-(tert-Butoxymethyl)-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-223)

EXAMPLE 37 was prepared using the procedures from EXAMPLE 13 AlternatePreparation, Steps 7, 8, 10 and 11 usingO-(tert-butyl)-N-{[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}-L-serine inStep 7 and(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. ¹H NMR (500 MHz, CDCl₃, ppm) δ 10.00 (s, 1 H), 7.27(t, J=7.0 Hz, 1 H), 7.20 (d, J=7.0 Hz, 1 H), 7.10 (d, J=7.0 Hz, 1 H),6.90 (s, 1 H), 6.25 (d, J=16.0 Hz, 1 H), 6.00 (m, 1 H), 5.85 (m, 1 H),5.60 (d, J=9.0 Hz, 1 H), 5.31 (m, 2 H), 5.17 (d, J=10.0 Hz, 1 H),4.81-4.85 (m, 1 H), 4.65-4.75 (m, 3 H), 4.60 (d, J=11.0Hz, 1 H),4.47-4.54 (m, 2 H), 4.15 (d, J=13.5 Hz, 1 H), 3.82 (m, 1 H), 3.70 (m, 1H), 3.57 (t, J=9.0 Hz, 1 H), 3.30 (d, J=11.0 Hz, 1 H), 2.91-2.95 (m, 1H), 2.18-2.29 (m, 3 H), 1.95-1.97 (m, 1 H), 1.54 (s, 6 H), 1.42-1.46 (m,1 H), 1.38-1.40 (m, 1 H), 1.26-1.34 (m, 3 H), 1.21 (s, 9 H), 0.99 (s, 3H), and 0.87 (br s, 3 H). LRMS (ESI) m/z 784.4 [(M+H)⁺; calcd forC₃₉H₅₃N₅O₁₀S: 784.4].

EXAMPLE 38(5R,7S,10S)-10-(tert-Butoxymethyl)-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5.8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-224)

EXAMPLE 38 was prepared from EXAMPLE 37 using the procedure describedfor EXAMPLE 8. ¹H NMR (500 MHz, CDCl₃, ppm) δ 10.00 (s, 1 H), 7.20 (t,J=7.5 Hz, 1 H), 7.10 (d, J=8.0 Hz, 1 H), 7.05 (d, J=8.5 Hz, 1 H), 6.82(s, 1 H), 5.54 (d, J=9.5 Hz, 1 H), 5.31 (m, 1 H), 4.80 (m, 1 H),4.68-7.76 (m, 2 H), 4.45-4.56 (m, 4 H), 4.17 (d, J=11.5 Hz, 1 H), 3.78(m, 1 H), 3.68-3.70 (m, 1 H), 3.58 (t, J=9.0 Hz, 1 H), 3.25 (d, J=11.0Hz, 1 H), 2.95-2.98 (m, 1 H), 2.71-2.75 (m, 1 H), 2.49-2.51 (m, 1 H),2.37-2.42 (m, 1 H), 1.64-1.71 (m, 3 H), 1.54 (s, 9 H), 1.45-1.33 (m, 3H), 1.26-1.33 (m, 5 H), 1.20 (s, 6 H), 1.00 (t, J=7.0 Hz, 2 H), 0.96 (s,2 H), and 0.80 (br s, 2 H). LRMS (ESI) m/z 788.4 [(M+H)⁺; calcd forC₃₉H₅₇N₅O₁₀S: 788.4].

EXAMPLE 39(5R,7S,10S,18E)-10-Cyclohexyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-225)

EXAMPLE 39 was prepared using the procedures from EXAMPLE 13 AlternatePreparation, Steps 7, 8, 10 and 11 using(2S)-cyclohexyl({[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}amino)aceticacid in Step 7 and(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. ¹H NMR (500 MHz, CD₃OD, ppm) δ 7.26 (m, 1 H), 7.20(t, J=7.5 Hz, 1 H), 7.15 (d, J=9.5 Hz, 1 H), 6.38 (d, J=9.5 Hz, 1 H),5.99-6.02 (m, 1 H), 5.74-5.80 (m, 1 H), 5.29-5.34 (m, 2 H), 5.11-5.14(m, 1 H), 4.79-4.81 (m, 2 H), 4.64-4.72 (m, 3 H), 4.56 (d, J=11.5 Hz, 1H), 4.36-4.40 (m, 2 H), 4.18 (d, J=11.5 Hz, 1 H), 4.10 (d, J=5.5 Hz, 0.5H), 3.91-3.94 (dd, J=11.5, 3.5 Hz, 1 H), 3.34 (d, J=11.0 Hz, 1 H),2.95-2.97 (m, 1 H), 2.52-2.56 (m, 1 H), 2.16-2.35 (m, 5 H), 1.65-1.82(m, 8 H), and 0.85-1.43 (m, 17 H). LRMS (ESI) m/z 780.4 [(M+H)⁺; calcdfor C₄₀H₅₃N₅O₉S: 780.9].

EXAMPLE 40(5R,7S,10S)-10-Cyclohexyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-226)

EXAMPLE 40 was prepared from EXAMPLE 39 using the procedure describedfor EXAMPLE 8. ¹H NMR (500 MHz, CDCl₃, ppm) δ 10.13 (s, 1 H), 7.22 (t,J=7.5 Hz, 1 H), 7.10 (d, J=7.5 Hz, 1 H), 7.05 (d, J=7.5 Hz, 1 H), 6.73(s, 1 H), 5.40 (d, J=9.5 Hz, 1 H), 5.36 (m, 1 H), 4.67-4.76 (m, 2 H),4.55 (d, J=15.5 Hz, 1 H), 4.44 (d, J=14.5 Hz, 1 H), 4.41 (d, J=11.0 Hz,1 H), 4.29-4.39 (m, 2 H), 4.16 (d, J=11.0 Hz, 1 H), 3.82-3.85(dd,J=11.5, 3.5 Hz, 1 H), 3.25 (d, J=11.0 Hz, 1 H), 2.95 (m, 1 H), 2.51-2.59(m, 2 H), 2.36-2.44 (m, 2 H), 1.73-1.76 (m, 5 H), and 0.79 (br s, 2 H).LRMS (ESI) m/z 784.4 [(M+H)⁺; calcd for C₄₀H₅₇N₅O₉S: 784.4].

EXAMPLE 41(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-17,18-didehydro-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(III-227)

Step 1: 1-tert-Butyl2-methyl-(2S,4R)-4-}[(4-bromo-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate

1-tert-Butyl2-methyl-(2S,4R)-4-{[(4-bromo-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylatewas prepared according to the procedure described in EXAMPLE 3, Step 5using 4-bromoisoindoline instead of 4-vinylisoindoline. LRMS (ESI) m/z370.2 [(M-Boc+H)⁺; calcd for C₁₅H₁₈BrN₂O₄: 370.3].

Step 2:N-[({5-[2-({[(3R,5S)-1-(tert-Butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-yl]oxy}carbonyl)-2,3-dihydro-1H-isoindol-4-yl]pent-4-yn-1-yl{oxy)carbonyl]-3-methyl-L-valine

A solution of 1-tert-butyl2-methyl-(2S,4R)-4-{[(4-bromo-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate(100 mg, 0.21 mmol) and3-methyl-N-[(pent-4-yn-1-yloxy)carbonyl]-L-valine (103 mg, 0.43 mmol) inTHF (1 mL) and pyrrolidine (1 mL) was purged with nitrogen. Copperiodide (4 mg, 0.02 mmol) and Pd(PPh₃)₄ (25 mg, 0.02 mmol) were added andthe reaction mixture was heated for 30 min at 70° C. under nitrogen. Theresulting mixture was poured into saturated aqueous NaHCO₃ and EtOAc,the organic layer separated and washed twice with 10% citric acidsolution, then brine and dried over Na₂SO₄. The residue was purified bycolumn chromatography on silica gel (eluting with 90:10:1DCM:MeOH:NH₄OH) and concentrated to giveN-[({5-[2-({[(3R,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-yl]oxy}carbonyl)-2,3-dihydro-1H-isoindol-4-yl]pent-4-yn-1-yl}oxy)carbonyl]-3-methyl-L-valine(131 mg, 99% yield) as colorless oil. LRMS (ESI) m/z 530.5 [(M+H)⁺;calcd for C₂₇H₃₆N₃O₈: 530.6].

Step 3: Methyl(5R,7S,10S)-10-tert-butyl-3,9,12-trioxo-17,18-didehydro-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate

A solution ofN-[({5-[2-({[(3R,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-yl]oxy}carbonyl)-2,3-dihydro-1H-isoindol-4-yn-1-yl}oxy)carbonyl]-3-methyl-L-valine(131 mg, 0.21 mmol) in DCM was saturated with HCl gas and stirred for 30min. The resulting amino acid,N-[({5-[2-({[(3R,5S)-5-(methoxycarbonyl)pyrrolidinium-3-yl]oxy}carbonyl)-2,3-dihydro-1H-isoindol-4-yl]pent-4-yn-1-yl}oxy)carbonyl]-3-methyl-L-valine,was obtained through removal of the solvent.

To a solution of this crude amine (120 mg, 0.21 mmol) and Et₃N (86 mg,0.85 mmol) in 5 mL of DCM was added HATU (81 mg, 0.21 mmol) and DMAP (1mg, 0.008 mmol). The resulting solution was stirred for 2 h at 25° C.,then the solvent was evaporated. The crude product was partitionedbetween 10% aqueous citric acid and EtOAc, the organic layer dried overNa₂SO₄ and concentrated to an oil. The residue was purified by columnchromatography on silica gel (gradient elution, 10 to 70% EtOAc inhexanes) and concentrated to givemethyl-(5R,7S,10S)-10-tert-butyl-3,9,12-trioxo-17,18-didehydro-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate(47 mg, 43% yield) as a colorless oil. LRMS (ESI) m/z 512.5 [(M+H)⁺;calcd for C₂₇H₃₄N₃O₇: 512.6].

Step 4:(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-17,18-didehydro-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(III-227)

EXAMPLE 41 was prepared frommethyl-(5R,7S,10S)-10-tert-butyl-3,9,12-trioxo-17,18-didehydro-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylateaccording to the procedures given in EXAMPLE 13 Alternative Preparation,Steps 10 and 11 using(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. ¹H NMR (400 MHz, CDCl₃, ppm) δ 7.25-7.17 (m, 3 H),7.09 (br s, 1 H), 5.80-5.71 (m, 1 H), 5.45 (d, J=9.8 Hz, 1 H), 5.41 (s,1 H), 5.23 (d, J=17.2 Hz, 1 H), 5.13 (d, J=9.6 Hz, 1 H), 4.82 (m, 3 H),4.69-4.44 (m, 3 H), 4.38 (m, 2 H), 3.99 (m, 1 H), 3.81 (dd, J=11.2, 2.8Hz, 1 H), 2.89 (m, 1 H), 2.80 (s, 1 H), 2.69-2.58 (m, 1 H), 2.53 (m, 1H), 2.48 (m, 1 H), 2.33 (m, 1 H), 2.15-2.08 (m, 1 H) 1.94 (t, J=5.9 Hz,2 H) 1.83-1.75 (m, 1 H), 1.46 (td, J=5.9, 3.3 Hz, 1 H), 1.37 (m, 1 H),1.06 (s, 9 H), and 1.02 (m, 3 H). LRMS (ESI) m/z 710.4 [(M+H)⁺; calcdfor C₃₅H₄₄N₅O₉S: 710.8].

EXAMPLE 42(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-18,19-didehydro-6,7,9,10,11,12,14,15,16,17-decahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-228)

EXAMPLE 42 was prepared according to the procedure described for EXAMPLE41 except that N-[(hex-5-yn-1-yloxy)carbonyl]-3-methyl-L-valine was usedinstead of 3-methyl-N-[(pent-4-yn-1-yloxy)carbonyl]-L-valine in Step 1.¹H NMR (400 MHz, DMSO-d₆, ppm) δ 7.95 (s, 1 H), 7.29 (m, 2 H), 6.98 (d,J=8.4 Hz, 1 H), 6.02 (m, 1 H), 5.23 (m, 1 H), 5.10-4.92 (m, 1 H), 4.84(m, 1 H), 4.66 (m, 2 H), 4.57-4.40 (m, 4 H), 4.26 (m, 1 H), 4.19 (d,J=8.8 Hz, 1 H), 4.01 (m, 1 H), 3.84 (m, 1 H), 3.62 (m, 1 H), 2.74-2.62(m, 1 H), 2.34-2.24 (m, 1 H), 2.19 (m, 1 H), 1.92 (m, 1 H), 1.70-1.62(m, 2 H), 1.59-1.42 (m, 4 H), 1.21 (m, 2 H), 0.97 (s, 9 H), and0.79-0.58 (m, 4 H). LRMS (ESI) m/z 724.3 [(M+H)⁺; calcd for C₃₆H₄₆N₅O₉S:724.8].

EXAMPLE 43(5R,7S,10S,17E)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-21-fluoro-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(III-15)

Step 1: 1-Bromo-2,3-bis(bromomethyl)-4-fluorobenzene

6-Bromo-3-fluoro-o-xylene (5.00 g, 24.6 mmol) was dissolved in 75 mLcarbon tetrachloride. N-Bromosuccinimide (8.76 g, 49.2 mmol) and benzoylperoxide (0.089 g, 0.37 mmol) were added and the resulting whitesuspension was refluxed for 18 h. The reaction mixture was filtered andthe filtrate concentrated to an oily suspension. The residue waspurified by column chromatography on silica gel (eluting with hexanes)and concentrated to give 1-bromo-2,3-bis(bromomethyl)-4-fluorobenzene(8.40 g, 94% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃, ppm) δ7.55 (dd, J=8.9, 5.2 Hz, 1 H), 6.97 (t, J=8.9 Hz, 1 H), 4.78 (s, 3 H),and 4.67 (s, 3 H).

Step 2: 2-Benzyl-4-bromo-7-fluoroisoindoline

To a mixture of 1-bromo-2,3-bis(bromomethyl)-4-fluorobenzene (7.59 g,21.0 mmol) and potassium hydrogen carbonate (5.26 g, 52.6 mmol) in 800mL CH₃CN was added benzylamine (2.25 g, 21.0 mmol). The resultingsuspension was refluxed for 8 h then stirred at 25° C. for 18 h. Themixture was filtered, and the residue was purified by columnchromatography on silica gel (gradient elution, 10 to 60% DCM inhexanes) and concentrated to give 2-benzyl-4-bromo-7-fluoroisoindoline(3.00 g, 46% yield) as colorless oil. LRMS (ESI) m/z 306.3 [(M+H)⁺;calcd for C₁₅H₁₄NBrF: 306.2].

Step 3:(5R,7S,10S,17E)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-21-fluoro-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16-decahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(III-15)

EXAMPLE 43 was prepared from 2-benzyl-4-bromo-7-fluoroisoindoline usingthe procedures described in EXAMPLE 3, Steps 3-6 and EXAMPLE 13Alternative Preparation, Steps 7, 8, 10 and 11, using3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine in Step 7 and(1R,2S)-1-{[(cyclopropyl-sulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. ¹H NMR (400 MHz, CDCl₃, ppm) δ 9.86 (s, 1 H), 7.24(m, 1 H), 7.20 (m, 1 H), 6.91 (t, J=8.6 Hz, 1 H), 6.25 (d, J=16.6 Hz, 1H), 5.99-5.90 (m, 1 H), 5.78-5.64 (m, 1 H), 5.43 (m, 2 H), 5.25 (d,J=16.6 Hz, 1 H), 5.15 (d, J=10.3 Hz, 1 H), 4.74 (m, 2 H), 4.67 (d,J=15.4 Hz, 1 H), 4.54 (m, 1 H), 4.47 (t, J=8.8 Hz, 1 H), 4.39-4.31 (m, 2H), 4.30-4.22 (m, 1 H), 3.88 (m, 1 H), 3.75 (dd, 1 H), 2.95-2.85 (m, 1H), 2.50-2.39 (m, 2 H) 2.30-2.21 (m, 2 H), 2.15 (m, 1 H), 1.97-1.92 (m,2 H), 1.72 (m, 1 H), 1.44 (dd, J=9.7, 5.8 Hz, 1 H), 1.31 (m, 2 H), and1.08 (m, 11 H). LRMS (ESI) m/z 730.4 [(M+H)⁺; calcd for C₃₅H₄₅FN₅O₉S:730.8].

EXAMPLE 44(5R,7S,10S)-10-tert-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-21-fluoro-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16,17,18-dodecahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(III-229)

EXAMPLE 44 was prepared from EXAMPLE 43 using the procedure describedfor EXAMPLE 8. ¹H NMR (400 MHz, CDCl₃, ppm) δ 9.88 (s, 1 H), 7.03 (m, 1H), 6.92 (d, J=8.5 Hz 1 H), 6.88 (d, J=7.8 Hz, 1 H), 5.60 (s, 1 H), 5.37(d, J=9.7 Hz, 1 H), 4.83-4.71 (m, 1 H), 4.61 (m, 2 H), 4.47-4.23 (m, 4H), 3.80-3.73 (m, 2 H), 2.99-2.81 (m, 1 H), 2.61-2.54 (m, 1 H),2.42-2.31 (m, 3 H), 1.82-1.62 (m, 9 H), 1.59-1.52 (m, 2 H), 1.38-1.29(m, 5 H), 1.04 (s, 9 H), and 0.97 (t, J=7.4 Hz, 3 H). LRMS (ESI) m/z734.4 [(M+H)⁺; calcd for C₃₅H₄₉FN₅O₉S: 734.8].

EXAMPLE 45(5R,7S,10S-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-21-methoxy-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16,17,18-dodecahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(III-230)

Step 1: 2-Benzyl-4-bromo-7-methoxyisoindoline

To a solution of methyl 1-bromo-2,3-bis(bromomethyl)-4-methoxybenzene(prepared as described in J. Org. Chem. 1992, 57, 6374, fromcommercially available 1-bromo-4-methoxy-2,3-dimethylbenzene) in CH₃CN(0.1 M) were added 2.5 eq of KHCO₃ and the mixture heated at 60° C. Then1 eq. of benzylamine in CH₃CN (0.9 M) was added within 15 minutes andthe mixture was heated to reflux for 2 h. The reaction mixture wasallowed to cool, filtered over celite and concentrated in vacuo. Thecrude material was purified by flash chromatography on silica gel (5%EtOAc in petroleum ether, then 10%) to afford the title compound (55%).¹H NMR (300 MHz, CDCl₃, ppm) δ 3.77 (s, 3H), 3.92 (s, 2H), 3.98 (s, 2H),4.01 (s, 2H), 6.60 (d, J 8.6, 1H), and 7.22-7.46 (m, 6H). MS (ES⁺) m/z318, 320 (M+H)⁺.

Step 2: (3R,5S)-5-(Methoxycarbonyl)pyrrolidin-3-yl4-methoxy-7-vinyl-1,3-dihydro-2H-isoindole-2-carboxylate hydrochloride

1-tert-Butyl 2-methyl(2S,4R)-4-{[(4-methoxy-7-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylatewas prepared from 2-benzyl-4-bromo-7-methoxy isoindoline using theprocedures described in EXAMPLE 3, Steps 3-5 and was converted to(3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl4-methoxy-7-vinyl-1,3-dihydro-2H-isoindole-2-carboxylate hydrochlorideusing the following procedure. To a solution of 1-tert-butyl 2-methyl(2S,4R)-4-{[(4-methoxy-7-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylatein CH₃OH (0.06 M) cooled at 0° C. was added acetyl chloride (70 eq). Theresulting mixture was stirred at 5° C. for 4 h and then concentrated invacuo at 0° C. affording the crude product, which was used straightawaywithout any further purification. MS (ES⁺) m/z 347 (M+H)⁺.

Step 3:(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-21-methoxy-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16,17,18-dodecahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxamide(III-230)

EXAMPLE 45 was prepared from (3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl4-methoxy-7-vinyl-1,3-dihydro-2H-isoindole-2-carboxylate hydrochlorideusing the procedures described in EXAMPLE 13 Alternative Preparation,Steps 7 through 11, using 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valinein Step 7 and(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.46 (s, 1H),8.85 (s, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 6.85 (d,J=8.3 Hz, 1H), 5.63-5.54 (m, 1H), 5.25 (s, 1H), 5.22 (d, J=18.2 Hz, 1H),5.10 (d, J=11.8 Hz, 1H), 4.64 (d, J=14.2 Hz, 1H), 4.56 (d, J=13.5 Hz,1H), 4.52 (d, J=13.5 Hz, 1H), 4.50 (d, J=14.2 Hz, 1H), 4.33 (dd, J=10.7Hz, 6.8 Hz, 1H), 4.23-4.18 (m, 2H), 4.12-4.10 (m, 1H), 3.78 (s, 3H),3.75-3.71 (m, 2H), 2.96-2.90 (m, 1H), 2.50 (obscured by residual DMSO,1H), 2.33-2.23 (m, 2H), 2.18-2.11 (m,1H), 2.06-2.01 (m, 1H), 1.71-1.69(m,1H), 1.68-1.62 (m, 1H), 1.53-1.43 (m, 3H), 1.37-1.22 (m, 3H),1.10-1.07 (m, 2H), 1.05-1.02 (m, 2H), and 1.00-0.86 (m, 9H). LRMS (ESI)m/z 744 [(M+H)⁺; calcd for C₃₆H₅₀N₅O₁₀S: 744.3].

EXAMPLE 46(5R,7S,10S)-10-tert-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23-ethano-5,8-methano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-231)

Step 1: 8-Hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide

A mixture of 8-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride[Tetrahedron Letters, 1991, 32(17), 1965.] (3.0 g 15.0 mmol) and 45 mLof 48% aqueous HBr was heated for 18 h at 120° C. The resulting brownsuspension was filtered and dried to provide8-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (2.8 g, 81%yield). LRMS (ESI) m/z 150.1 [(M+H)⁺; calcd for C₉H₁NO: 150.2].

Step 2: 1-tert-Butyl 2-methyl(2S,4R)-4-{[(8-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate:

Carbonyldiimidazole (0.176 g, 1.086 mmol) was added to a stirred, roomtemperature solution of DMF (5 mL) and N-Boc-trans-4-hydroxy-L-prolinemethyl ester (0.21 g, 0.87 mmol) and the mixture was stirred 45 min.8-Hydroxy-1,2,3,4-tetrahydroisoquinoline (0.20 g, 0.87 mmol) and Et₃N(0.18 g, 1.74 mmol) were added and the resulting solution was heated at50° C. for 2 h. The reaction mixture was poured into aqueous saturatedNH₄Cl and extracted with EtOAc, dried over Na₂SO₄ and concentrated to anoil. The residue was purified by column chromatography on silica gel(gradient elution, 10 to 80% EtOAc in hexanes) to give 1-tert-butyl2-methyl(2S,4R)-4-{[(8-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate(0.25 g, 0.60 mmol, 69% yield) as a colorless foam after evaporation ofsolvent. LRMS (ESI) m/z 321.3 [((M-Boc)+H)⁺; calcd for C₁₆H₂₁N₂O₅:321.4].

Step 3: 1-tert-Butyl 2-methyl(2S,4R)-4-({[8-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}oxy)pyrrolidine-1,2-dicarboxylate

Trifluoromethanesulfonic anhydride (1.76 g, 6.24 mmol) was added to astirred, 0° C. mixture of 1-tert-butyl 2-methyl(2S,4R)-4-{[(8-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate(1.81 g, 4.30 mmol) and Et₃N (1.31 g, 12.90 mmol) in DCM (20 mL) andstirred for 18 h. The resulting mixture was poured into saturatedaqueous NaHCO₃ and extracted into dichloromethane. The organic layer waswashed with 10% citric acid solution, dried over Na₂SO₄ and concentratedto red oil. The oil was purified by column chromatography on silica gel(gradient elution, 10 to 70% EtOAc in hexanes) to give a yellow oil,1-tert-butyl 2-methyl (2S,4R)-4-({[8-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}oxy)pyrrolidine-1,2-dicarboxylate(1.65 g, 69.4% yield). LRMS (ESI) m/z 453.2 [((M-Boc)+H)⁺; calcd forC₁₇H₂₀F₃N₂O₇S: 453.4].

Step 4: 1-tert-Butyl 2-methyl(2S,4R)-4-{[(8-vinyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate

A solution of 1-tert-butyl 2-methyl(2S,4R)-4-({[8-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}oxy)pyrrolidine-1,2-dicarboxylate(1.74 g, 3.15 mmol), tri-n-butyl vinyl tin (1.10 g, 1.46 mmol) andlithium chloride (0.40 g, 9.45 mmol) in 25 mL DMF was purged withnitrogen for 10 min. Then bis(triphenylphosphine)palladium (II) chloride(0.22 g, 0.32 mmol) was added, and the mixture stirred at 25° C. undernitrogen for 18 h. The mixture was partitioned between EtOAc andsaturated NaHCO₃, the organic layer separated and washed with water thenbrine, dried over anhydrous sodium sulfate and concentrated to an oil.The oil was purified by column chromatography on silica gel (gradientelution, 10 to 65% EtOAc in hexanes) to give a colorless oil,1-tert-butyl 2-methyl(2S,4R)-4-{[(8-vinyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate(1.00 g, 74% yield). LRMS (ESI) m/z 453.2 [(M+Na)⁺; calcd forC₂₃H₃₀N₂O₆Na: 453.5].

Step 5:(5R,7S,10S)-10-tert-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23-ethano-5.8-methano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-231)

EXAMPLE 46 was prepared from 1-tert-butyl 2-methyl(2S,4R)-4-{[(8-vinyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylateusing the procedures described in EXAMPLE 3, Step 6 followed by EXAMPLE13 Alternative Preparation, Steps 7 through 11. ¹H NMR (400 MHz, CDCl₃,ppm) δ 9.02 (s, 1 H), 7.13 (m, 1 H), 7.08 (d, J=7.7 Hz, 1 H), 7.02 (d,J=7.3 Hz, 1 H), 6.97 (d, J=7.7 Hz, 1 H), 6.96 (m, 1 H), 5.36 (s, 1 H),4.68 (d, J=16.3 Hz, 1 H), 4.60-4.31 (m, 3 H), 4.25 (m, 1 H), 4.18 (m, 1H), 4.11-3.94 (m, 2 H), 3.47 (q, J=7.0 Hz, 2 H), 2.91 (m, 1 H), 2.80 (m,2 H), 2.52 (m, 1 H), 2.41-2.28 (m, 2 H), 2.11 (td, 1 H), 1.60-1.52 (m, 3H), 1.51 (m, 4 H), 1.32 (m, 3 H), 1.24 (m, 3 H), 1.21 (t, J=7.0 Hz, 3H), 1.09 (m, 2 H), 1.03 (s, 9 H), 0.93 (s, 3 H), and 0.82 (s, 3 H). LRMS(ESI) m/z 772.5 [(M+H)⁺; calcd for C₃₉H₅₈N₅O₉S: 773.0].

EXAMPLE 47(5R,7S,10S,17E)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-13-isopropyl-3,9,12-trioxo-6,7,9,10,11,12,13,14,15,16-decahydro-1H,5H-2,22:5,8-dimethano-4,2,8,11,13-benzoxatetraazacycloicosine-7-carboxamide(III-232)

EXAMPLE 47 was prepared using the procedures from EXAMPLE 13 AlternatePreparation, Steps 7, 8, 10 and 11 usingN-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valine in Step 7and(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. ¹H-NMR (400 MHz, DMSO, ppm) δ 10.48 (s, 1H), 7.35(d, J=7.7 Hz, 1H), 7.36 (t, J=6.7 Hz, 1H), 7.18 (d, J=7.7 Hz, 1H), 6.58(d, J=16.1 Hz, 1H), 6.35-6.27 (m, 1H), 6.38-5.57 (m, 1H), 5.25-5.18 (m,2H), 5.09 (dd, J=12.0 Hz, 1H), 4.98 (d, J=12.0 Hz, 1H), 4.90-4.84 (m,1H), 4.68-4.57 (m, 3H), 4.30-4.24 (m, 3H), 4.13 (d, J=8.8 Hz, 1H),4.07-3.95 (m, 1H), 3.70 (d, J=12.8 Hz, 1H), 3.38-3.27 (m, 1H), 2.94-2.87(m, 1H), 2.37-1.99 (m, 5H), 1.97-1.88 (m, 1H), 1.70 (dd, J₁=9.6 Hz,J₂=4.0 Hz, 1H), 1.58-1.52 (m, 1H), 1.47 (dd, J₁=9.6 Hz, J₂=4.0 Hz, 1H),1.20-1.13 (m, 6H), and 1.07-0.98 (m, 13H). LRMS (ESI) m/z 753 [(M+H)⁺;calcd for C₃₈H₅₃N₆O₈S: 753.4].

EXAMPLE 48(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-13-isopropyl-3,9,12-trioxo-6,7,9,10,11,12,13,14,15,16,17,18-dodecahydro-1H,5H-2,22:5,8-dimethano-4,2,8,11,13-benzoxatetraazacycloicosine-7-carboxamide(III-233)

EXAMPLE 48 was prepared using the procedures from EXAMPLE 13 AlternatePreparation, Steps 7 through 11 usingN-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valine in Step 7and(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. ¹H-NMR (400 MHz, DMSO, ppm) δ 10.50 (s, 1H), 9.06(s, 1H), 7.26-7.22 (m, 1H), 7.16-7.11 (m, 2H), 5.68-5.59 (m, 1H), 5.34(bs, 1H), 5.22 (d, J=17.3 Hz, 1H), 5.11-5.08 (m, 2H), 4.73-4.54 (m, 5H),4.33 (dd, J₁=10.9 Hz, J₂=6.6 Hz, 1H), 4.16 (d, J=9.4 Hz, 2), 3.95-3.90(m, 1H), 3.73-3.71(m, 1H), 3.08-3.04 (m, 1H), 2.95-2.86 (m, 2H),2.66-2.58 (m, 1H), 2.35-2.28 (m, 2H), 2.16-2.09 (m, 2H), 1.70 (dd,J₁=7.9 Hz, J₂=5.2 Hz, 1H), 1.58-1.45 (m, 3H), 1.39-1.36 (m, 2H),1.31-1.21 (m, 1H), 1.16-1.10 (m, 6H), 1.09-1.01 (m, 4H), and 0.98 (s,9H). LRMS (ESI) m/z 755 [(M+H)⁺; calcd for C₃₈H₅₅N₆O₈S: 755.4].

EXAMPLE 49(5R,7S,10S,18E)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-13-isopropyl-3,9,12-trioxo-1,6,7,9,10,11,12,13,14,15,16,17-dodecahydro-5H-2,23:5,8-dimethano-4,2,8,11,13-benzoxatetraazacyclohenicosine-7-carboxamide(III-234)

EXAMPLE 49 was prepared using the procedures from EXAMPLE 13 AlternatePreparation, Steps 7, 8, 10 and 11 usingN-{[hex-5-en-1-yl(isopropyl)amino]carbonyl}-3-methyl-L-valine in Step 7and(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. ¹H-NMR (400 MHz, DMSO, ppm) δ 10.55 (s, 1H), 9.06(s, 1H), 7.30-7.20 (m, 3H), 6.36 (d, J=16.4 Hz, 1H), 6.04 (m, 1H),5.72-5.63 (m, 1H), 5.30-5.21 (m, 3H), 5.09 (d, J=11.9 Hz, 1H), 4.70-4.57(m, 4H), 4.34 (d, J=9.1 Hz, 1H), 4.29 (dd, J=11.1, 6.4 Hz, 1H), 4.09 (d,J=11.9 Hz, 1H), 3.97-3.84 (m, 2H), 3.47-3.42 (m, 1H), 2.92-2.87 (m, 2H),2.35-2.20 (m, 2H), 2.17-2.02 (m, 3H), 1.69 (dd, J=8.08, 5.2 Hz, 1H),1.58 (m, 1H), 1.48-1.39 (m, 4H), 1.18 (d, J=6.6Hz, 3H), 1.14 (d, J=6.6Hz, 3H),), 1.11-1.02 (m, 3H), and 0.99 (s, 9H). LRMS (ESI) m/z 767[(M+H)⁺; calcd for C₃₉H₅₅N₆O₈S: 767.4].

EXAMPLE 50(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-13-isopropyl-3,9,12-trioxo-1,6,7,9,10,11,12,13,14,15,16,17,18,19-tetradecahydro-5H-2,23:5,8-dimethano-4,2,8,11,13-benzoxatetraazacyclohenicosine-7-carboxamide(III-235)

EXAMPLE 50 was prepared using the procedures from EXAMPLE 13 AlternatePreparation, Steps 7 through 11 usingN-{[hex-5-en-1-yl(isopropyl)amino]carbonyl}-3-methyl-L-valine in Step 7and(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. ¹H-NMR (400 MHz, DMSO+TFA, ppm) δ 10.52 (s, 1H),9.02 (s, 1H), 7.14 (m, 1H), 7.06 (d, J=7.6 Hz, 1H), 7.01 (d, J=7.1 Hz,1H), 5.7-5.59 (m, 1H), 5.26-5.16 (m, 3H), 5.02 (d, J=10.8 Hz, 1H),4.62-4.48 (m, 4H), 4.28 (m, 2H), 4.08 (d, J=11.9 Hz, 1H), 3.89-3.76 (m,2H), 3.42-3.31 (m, 1H), 2.89-2.75 (m, 2H), 2.6-2.29 (m, 5H), 2.12-1.98(m, 2H), 1.7 (m, 1H), 1.52-1.16 (m, 6H), 1.13-0.95 (m, 19H). LRMS (ESI)m/z 769 [(M+H)⁺; calcd for C₃₉H₅₇N₆O₈S: 769.4].

EXAMPLE 51(5R,7S,10S,17E)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-13-propyl-6,7,9,10,11,12,13,14,15,16-decahydro-1H,5H-2,22:5,8-dimethano-4,2,8,11,13-benzoxatetraazacycloicosine-7-carboxamide(III-236)

EXAMPLE 51 was prepared using the procedures from EXAMPLE 13 AlternatePreparation, Steps 7, 8, 10 and 11 using3-methyl-N-{[pent-4-en-1-yl(propyl)amino]carbonyl}-L-valine in Step 7and(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. ¹H-NMR (400 MHz, DMSO, ppm) δ 10.50 (s, 1H),9.01(s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.26 (t, J=8.6 Hz, 1H), 7.17 (d,J=8.4Hz, 1H), 6.53 (d, J=20.0 Hz, 1H)), 6.31 (dd, J₁=20 Hz, J₂=5.6 Hz,1H), 5.67-5.56 (m, 1H), 5.25-5.20 (m, 2H), 5.09 (dd, J=15.0 Hz, 1H),4.97-4.83 (m, 4H), 4.67-4.55 (m, 4H), 4.43-4.37 (m, 2H), 4.14 (d, J=10.7Hz, 1H), 3.68 (dd, J₁=12.0 Hz, J₂=4.0 Hz, 1H), 3.38-3.32 (m, 1H),3.23-3.05 (m, 3H), 2.95-2.87 (m, 1H), 2.34-1.97 (m, 4H), 1.85-1.52 (m,4H), 1.38-1.33 (m, 1H), 1.09-0.97 (m, 12H), and 0.98 (t, J=10.0 Hz, 3H).LRMS (ESI) m/z 753 [(M+H)⁺; calcd for C₃₈H₅₃N₆O₈S: 753.4].

EXAMPLE 52(5R,7S,10S)-10-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-13-propyl-6,7,9,10,11,12,13,14,15,16,17,18-dodecahydro-1H,5H-2,22:5,8-dimethano-4,2,8,11,13-benzoxatetraazacycloicosine-7-carboxamide(III-237)

EXAMPLE 52 was prepared using the procedures from EXAMPLE 13 AlternatePreparation, Steps 7 through 11 using3-methyl-N-{[pent-4-en-1-yl(propyl)amino]carbonyl}-L-valine in Step 7and(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminiumchloride in Step 11. ¹H-NMR (400 MHz, DMSO, ppm) δ 10.51 (s, 1H), 9.09(s, 1H), 7.27-7.22 (m, 1H), 7.18-7.10 (m, 2H), 5.20-5.10 (m, 1H), 5.38(bs, 1H), 5.25 (d, J=13 Hz, 1H), 5.05-5.12 (m, 2H), 4.52-4.68 (m, 4H),4.34 (dd, J₁=14 Hz, J₂=5 Hz, 1H), 4.20 (d, J=8 Hz, 1H), 4.12 (d, J=11Hz, 1H), 3.74 (dd, J₁=12 Hz, J₂=5 Hz, 1H), 3.42-3.34 (m, 1H), 3.11 (t,J=12 Hz, 2H), 2.92-2.83 (m, 2H), 2.63-2.56 (m, 1H), 2.37-2.25 (m, 2H),2.18-2.05 (m, 2H), 1.76-1.70 (m, 1H), 1.60-1.45 (m, 5H), 1.42-1.36 (m,2H), 1.24-1.12 (m, 2H), 1.10-1.03 (m, 4H), 0.88 (s, 9H), and 0.87 (t,J=7 Hz, 3H). LRMS (ESI) m/z 755 [(M+H)⁺; calcd for C₃₈H₅₅N₆O₈S: 755.4].

EXAMPLE 53(5R,7S,10S)-10-tert-Butyl-N-[(1R,2S)-1-({[(dimethylamino)sulfonyl]amino}carbonyl)-2-vinylcyclopropyl]-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5,8-dimethano-4.13,2.8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-238)

To a solution of(5R,7S,10S)-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxylicacid (EXAMPLE 13 Alternative Preparation, Step 10) (200 mg, 0.306 mmol),N,N-dimethylsulfamide (TCI Industries, 152 mg, 1.226 mmol), DIPEA (0.268mL, 1.532 mmol), and DMAP (150 mg, 1.226 mmol) in DMF (6 mL) was addedDBU (0.208 mL, 1.379 mmol) and the mixture was stirred for 5 min. HATU(128 mg, 0.337 mmol) was added and the mixture was stirred for 18 h.Additional HATU (40 mg, 0.150 mmol) was added and the reaction wasstirred an additional 24 h. The reaction mixture was purified by reversephase chromatography to give EXAMPLE 53 (130 mg) as a white foam. ¹H NMR(500 MHz, CDCl₃, ppm) δ 9.77 (s, 1 H), 7.22 (t, J=7.6 Hz, 1 H), 7.09 (d,J=7.6 Hz, 1 H), 7.05 (d, J=7.3 Hz, 1 H), 6.86 (s, 1 H), 5.74 (m, 1H),5.57 (d, J=13.7 Hz,1 H), 5.34 (m, 1 H), 5.24 (dd, J=0.7 and 17.2 Hz, 1H), 5.15 (dd, J=1.5 and 10.3 Hz, 1 H), 4.72 (q, J=14.7 Hz, 2H), 4.3-4.6(m, 6 H), 4.18 (d, J=10.7 Hz, 1 H), 3.84 (dd, J=3.4 and 11.7 Hz, 1 H),3.26 (d, J=10.7 Hz, 1 H), 2.90 (s, 6 H), 2.70-1.70 (m, 6 H), 1.60-1.20(m, 5 H), 1.30 (m, 1 ), 1.05 (m, 9 H), 0.96 (s, 3 H), and 0.79 (s, 3 H).LRMS (ESI) m/z 759.6 [(M+H)⁺; calcd for C₃₇H₅₅N₆O₉S: 759.4].

EXAMPLE 54(5R,7S,10S)-10-tert-Butyl-15,15-dimethyl-3,9,12-trioxo-N-((1R,2S)-1-{[(piperidin-1-ylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-239)

EXAMPLE 54 was prepared according to the procedure used for EXAMPLE 53except that piperidine-1-sulfonamide [Bioorg. Med. Chem. Lett., 2003,(13), 837.] was used in place of N,N-dimethylsulfamide. ¹H NMR (500 MHz,CDCl₃, ppm) δ 9.72 (s, 1 H), 7.21 (t, J=7.6 Hz, 1 H), 7.09 (d, J=7.6 Hz,1 H), 7.05 (d, J=7.3 Hz, 1 H), 6.78 (s, 1 H), 5.75 (m, 1H), 5.50 (d,J=13.7 Hz,1 H), 5.32 (m, 1 H), 5.22(dd, J=0.7 and 17.2 Hz, 1 H), 5.14(dd, J=1.5 and 10.3 Hz, 1 H), 4.72 (q, J=14.7 Hz, 2H), 4.6-4.3 (m, 6 H),4.18 (d, J=10.7 Hz, 1 H), 3.84 (dd, J=3.4 and 11.7 Hz, 1 H), 3.40-3.20(m, 5 H), 2.60-2.20 (m, 4 H), 1.60-1.10 (m, 14 H), 1.40 (m, 9 H), 0.96(s, 3 H), and 0.79 (s, 3 H). LRMS (ESI) m/z 799.6 [(M+H)⁺; calcd forC₄₀H₅₉N₆O₉S: 799.4].

EXAMPLE 55(5R,7S,10S)—N-{(1R,2S)-1-[({[Benzyl(methyl)amino]sulfonyl}amino)carbonyl]-2-vinylcyclopropyl}-10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide(III-240)

EXAMPLE 55 was prepared according to the procedure used for EXAMPLE 53except that N-benzyl-N-methylsulfamide [J. Med. Chem., 1967, 10(4),636.] was used in place of N,N-dimethylsulfamide. ¹H NMR (500 MHz,CDCl₃, ppm) δ 9.95 (s, 1 H), 7.32 (m, 5 H), 7.22 (t, J=7.6 Hz, 1 H),7.09 (d, J=7.6 Hz, 1 H), 7.05 (d, J=7.3 Hz, 1 H), 6.85 (s, 1 H), 5.80(m, 1 H), 5.56 (d, J=9.8 Hz,1 H), 5.34 (m, 1 H), 5.26 (dd, J=0.9 and17.3 Hz, 1 H), 5.17 (dd, J=1.2 and 10.2 Hz, 1 H), 4.71 (q, J=14.8 Hz, 2H), 4.6-4.1 (m, 6 H), 4.18 (d, J=10.8 Hz, 1 H), 3.85 (dd, J=3.4 and 11.7Hz, 1 H), 3.25 (d, J=10.8 Hz, 1 H), 2.76 (s, 3 H), 2.63 (m, 1 H), 2.52(m, 1 H), 2.35 (m, 2 H), 2.10 (m, 2 H), 1.98 (m, 1 H), 1.48 (m, 3 H),1.30 (m, 3 H), 1.12 (m, 1 H), 1.03 (m, 9 H), 0.96 (s, 3 H), and 0.79 (s,3 H). LRMS (ESI) m/z 835.6 [(M+H)⁺; calcd for C₄₃H₅₉N₆O₉S: 835.4].

Alternative preparation of(1R,2R)-1-amino-N-(cyclopropylsulfonyl)-2-ethylcyclopropanecarboxamidehydrochloride

Step 1: tert-Butyl((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)carbamate

A hydrogenaton vessel was charged with a methanol (1000 mL) slurry oftert-butyl((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)carbamate(164 g, 0.50 mol) (Wang et al, U.S. Pat. No. 6,995,174) and 5% Ru/C(dry, 7.5 wt %, 12.4 g) and set stirring. The vessel was placed undernitrogen (20 psig) and vented to atmospheric pressure three times toremove residual oxygen. The vessel was then placed under hydrogen (50psig). After 20 hours, the vessel was vented to atmospheric pressure.The reaction slurry was then transferred out of the reaction andfiltered through SOLKA FLOK (34 grams, wetted w/100 mL methanol) toyield a clear, light brown solution. The SOLKA FLOK was rinsed withmethanol (200 mL×2). The combined methanol solutions were concentratedunder reduced pressure to yield crude product as a white solid (153 g).The crude product was slurried in ethyl acetate (800 mL), warmed to 40°C. and aged 30 minutes. The solution was then seeded, aged 30 minutes,and heptane (500 mL) was added via addition funnel over 30 minutes. Thepartially crystallized solid was cooled to room temperature and agedovernight after which additional heptane (500 mL) was added. After onehour, additional heptane (250 mL) was added via addition funnel, and thewhite slurry aged for one hour. The solution was filtered and the solidwas rinsed with heptane/EtOAc (500 mL, 4:1) and dried under reducedpressure to give tert-butyl((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)carbamate(125.9 g).

Step 2:(1R,2R)-1-amino-N-(cyclopropylsulfonyl)-2-ethylcyclopropanecarboxamidehydrochloride

A solution of the product from Step 1 above (92 g, 0.28 mol) in DCM(1200 mL) was cooled to 0° C. and HCl bubbled through the solution for10 min, the cooling bath removed and the recation mixture stirred for 2h. Nitrogen was bubbled through the reaction mixture for 5 min and thevolatiles evaporated. The residue was azeotroped with DCM (×3) to givean off white powder (75 g). LRMS (M+H)⁺ Calcd.=233; found 233.

Preparation ofN-{[(1-but-3-en-1-ylcyclohexyl)methoxy]carbonyl}-3-methyl-L-valine:

N-{[(1-But-3-en-1-ylcyclohexyl)methoxy]carbonyl}-3-methyl-L-valine wasprepared according to the procedure forN-{[(2,2-dimethylhex-5-enyl)oxy]carbonyl}-3-methyl-L-valine by usingmethyl cyclohexanecarboxylate instead of ethyl isobutyrate in Step 1.LRMS (ESI) m/z 326.3 [(M+H)⁺; calcd for C₁₈H₃₂NO₄: 326.2].

Preparation ofN-{[(1-but-3-en-1-ylcyclopentyl)methoxy]carbonyl}-3-methyl-L-valine:

N-{[(1-But-3-en-1-ylcyclopentyl)methoxy]carbonyl}-3-methyl-L-valine wasprepared according to the procedure forN-{[(2,2-dimethylhex-5-enyl)oxy]carbonyl}-3-methyl-L-valine by usingmethyl cyclopentanecarboxylate instead of ethyl isobutyrate in Step 1.LRMS (ESI) m/z 312.3 [(M+H)⁺; calcd for C₁₇H₃₀NO₄: 312.2].

Preparation ofN-{[(1-but-3-en-1-ylcyclobutyl)methoxy]carbonyl}-3-methyl-L-valine:

N-{[(1-But-3-en-1-ylcyclobutyl)methoxy]carbonyl}-3-methyl-L-valine wasprepared according to the procedure forN-{[(2,2-dimethylhex-5-enyl)oxy]carbonyl}-3-methyl-L-valine by usingethyl cyclobutanecarboxylate instead of ethyl isobutyrate in Step 1.LRMS (ESI) m/z 298.3 [(M+H)⁺; calcd for C₁₆H₂₈NO₄: 298.2].

Preparation ofN-{[(1-but-3-en-1-ylcyclopropyl)methoxy]carbonyl}-3-methyl-L-valine:

Step 1: Ethyl 2-(diethoxyphosphoryl)hex-5-enoate

To a stirred suspension of NaH (60% dispersion in mineral oil, 9.37 g,234 mmol) in dry THF (100 mL), at 22° C. and under nitrogen, was addeddropwise triethyl phosphonoacetate (26.5 mL, 134 mmol). Stirred for 30minutes, this reaction was added dropwise 4-bromo-1-butene (24.4 mL, 241mmol), then refluxed at 80° C. for 5 hours. Quenched at 22° C. with 1Naqueous NH₄Cl (40 mL), the reaction was then concentrated. The residuewas diluted with water (200 mL) and extracted with ether (3×200 mL). Thecombined ether layer was washed with water (70 mL), brine (70 mL), driedover Na₂SO₄, filtered and concentrated. The residue was flashchromatographed on 120 g silica gel 60, eluting with 20-90%EtOAc/Hexane, to give the title compound (17.5 g, 47.1%). LRMS (ESI) m/z279.3 [(M+H)⁺; calcd for C₁₂H₂₄O₅P: 279.1].

Step 2: Ethyl 1-but-3-en-1-ylcyclopropanecarboxylate

To a stirred suspension of NaH (60% dispersion in mineral oil, 3.02 g,75.5 mmol) in dry benzene (100 mL), at 22° C. and under nitrogen, wasadded dropwise ethyl 2-(diethoxyphosphoryl)hex-5-enoate with anhydrousEtOH (0.044 mL, 0.76 mmol) over 30 minutes. Stirred for 30 minutes, thisreaction, cooled at 0° C. and attached with a dry ice/acetone condenser,was added via cannula ethylene oxide (12.7 g, 289.3 mmol), then refluxedat 50° C. for 5 hours. Quenched at 22° C. with 1N aqueous NH₄Cl (100mL), the reaction solution was extracted with Et₂O (3×200 mL). Thecombined Et₂O layers were washed with aqueous saturated NaHCO₃ (100 mL),water (70 mL), brine (70 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was flash chromatographed on 120 g silica gel60, eluting with 20-100% EtOAc/Hexane, to give the title product (5.07g, 48%). LRMS (ESI) m/z 169.2 [(M+H)⁺; calcd for C₁₀H₁₇O₂: 169.1].

Step 3:N-{[(1-But-3-en-1-ylcyclopropyl)methoxy]carbonyl}-3-methyl-L-valine

N-{[(1-But-3-en-1-ylcyclopropyl)methoxy]carbonyl}-3-methyl-L-valine wasprepared according to the procedure forN-{[(2,2-dimethylhex-5-enyl)oxy]carbonyl}-3-methyl-L-valine (Steps 2 and3) by using ethyl 1-but-3-en-1-ylcyclopropanecarboxylate_instead ofethyl 2,2-dimethylhex-5-enoate in Step 2. LRMS (ESI) m/z 284.3 [(M+H)⁺;calcd for C₁₅H₂₆NO₄: 284.2].

Preparation of(2S)-(1-methylcyclohexyl){[(pent-4-en-1-yloxy)carbonyl]amino}aceticacid:

Step 1: 1-Methylcyclohexanecarboxaldehyde

To a solution of cyclohexanecarboxaldehyde (10.8 mL, 89.15 mmol) in DCM(500 mL) cooled to 0° C. was added potassium tert-butoxide (13.0 g,115.9 mmol) and methyl iodide (16.65 mL, 267.5 mmol). After 30 min atthis temperature, the mixture was warmed to RT and stirring wascontinued for an additional 5 h. The reaction was then poured into brineand extracted with DCM. The organic layer was dried over MgSO₄ and thesolvent was then removed carefully in vacuo to yield 9.4 g (83%) ofcrude 1-methylcyclohexanecarboxaldehyde which was ˜80% pure and was useddirectly in the next reaction.

Step 2: (2S)-Amino(1-methylcyclohexyl)acetic acid hydrochloride

Using the asymmetric Strecker method of Chakraborty (Chakraborty, T. K.,Hussain, K. A., Reddy, G. V.; Tetrahedron 51, 33, 1995, 9179-9190)(2S)-amino(1-methylcyclohexyl)acetic acid hydrochloride was prepared.

To a solution of (2S)-amino(1-methylcyclohexyl)acetic acid hydrochloride(9.3 g, 73.7 mmol) in CHCl₃ (700 mL) was added (R)-(−)-2-phenylglycinol(10.1 g, 73.7 mmol). After stirring for 1 h, the mixture was cooled to0° C. and trimethylsilylcyanide (19.65 mL, 147.4 mmol) was added. Thereaction was then warmed to RT and stirred for 2 d. Brine was then addedand the mixture was extracted with DCM. The organic layer was dried overMgSO₄ and the solvent was removes in vacuo to yield 28 g of crudesilylated material. The mixture was then taken up in DCM (250 mL) andstirred vigorously with 4 N HCl (100 mL) for 24 h. The organic layer wasthen washed with aq. NaHCO₃, dried over MgSO₄, and the solvent wasremoved in vacuo to yield 16 g of crude desilylated material. Theaqueous layer was then basified with concentrated NaOH and extractedwith EtOAc. The organic layer was then dried over MgSO4 and the solventwas removed in vacuo to yield 3.3 g of crude material. The combinedcrude material was purified on silica (isco, 120 g, 0-30% EtOac/hex) toyield 5.0 g (25%) of(2R)-{[(1R)-2-hydroxy-1-phenylethyl]amino}(1-methylcyclohexyl)acetonitrile.

To solution of(2R)-{[(1R)-2-hydroxy-1-phenylethyl]amino}(1-methylcyclohexyl)acetonitrile(4.8 g, 17.6 mmol) in DCM (100 mL) and MeOH (50 mL) cooled to 0° C. wasadded lead tetraacetate (9.37 g, 21.15 mmol). After 30 min, the reactionwas warmed to RT and stirred for 24 h. The mixture was then quenchedwith pH 7 phosphate buffer and stirred for 1 h. The solids were thenremoved by filtration, and the mixture was extracted with DCM. Theorganic layer was dried over MgSO₄ and the solvent was removed in vacuo.The crude material was then taken up in concentrated HCl (100 mL) andheated to reflux for 48 h. After cooling to RT, the aqueous layer waswashed with Et₂O 2× and DCM 3×. The water was then removed in vacuo (10mmHg at 50° C.) to yield (2S)-amino(1-methylcyclohexyl)acetic acid-HClsalt (3.35 g, 91%) as an off-white solid. LRMS (ESI) m/z 172.2 [(M+H)⁺;calcd for C₉H₁₇NO₂: 172.2].

Step 3:(2S)-(1-Methylcyclohexyl){[(pent-4-en-1-yloxy)carbonyl]amino}acetic acid

(2S)-(1-methylcyclohexyl){[(pent-4-en-1-yloxy)carbonyl]amino}acetic acidwas prepared according to the procedure for3-methyl-N-[(pent-4-en-1-yloxy)carbonyl]amino}acetic acid wasamino(1-methylcyclohexyl)acetic acid-HCl instead of t-butylglycine. LRMS(ESI) m/z 347.3 [(M+Na+CH3CN)⁺; calcd for C₁₇H₂₈N₂NaO₄: 347.2].

Preparation of(2S)-({[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}amino)(1-methylcyclohexyl)acetic:acid

(2S)-({[(2,2-Dimethylhex-5-en-1-yl)oxy]carbonyl}amino)(1-methylcyclohexyl)aceticacid was prepared according to the procedure for3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine using(2S)-amino(1-methylcyclohexyl)acetic acid-HCl and2,2-dimethylhex-5-en-1-ol. LRMS (ESI) m/z 326.3 [(M+H)⁺; calcd forC₁₈H₃₂NO₄: 326.2].

Preparation of(2S)-4,4,4-trifluoro-2-{[(hex-5-en-1-yloxy)carbonyl]amino}butanoic acid:

(2S)-4,4,4-trifluoro-2-{[(hex-5-en-1-yloxy)carbonyl]amino}butanoic acidwas prepared according to the procedure for3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine using(2S)-2-amino-4,4,4-trifluorobutanoic acid and 5-hexenol. LRMS (ESI) m/z284.3 [(M+H)⁺; calcd for C₁₁H₁₇F₃NO₄: 284.1].

Preparation ofO-(tert-butyl)-N-{[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}-L-serine:

O-(tert-Butyl)-N-{[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}-L-serine wasprepared according to the procedure for3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine usingO-(tert-butyl)-L-serine and 2,2-dimethylhex-5-en-1-ol. ¹H NMR (500 MHz,CDCl₃, ppm) δ 5.75-5.86 (m, 1 H), 4.90-5.04 (m, 2 H), 4.02 (m, 1 H),3.57-3.90 (m, 4 H), 1.98-2.05 (m, 2 H), 1.27-1.36 (m, 2 H), 1.14 (s, 9H), 1.01 (d, J=6.5 Hz, 1 H), and 6.09 (s, 6 H).

Preparation of(2S)-cyclohexyl({[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}amino)aceticacid:

(2S)-Cyclohexyl({[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}amino)aceticacid was prepared according to the procedure for3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine using(2S)-amino(cyclohexyl)acetic acid and 2,2-dimethylhex-5-en-1-ol. LRMS(ESI) m/z 312.3 [(M+H)⁺; calcd for C₁₇H₃₀NO₄: 312.2].

Preparation of 3-methyl-N-[(pent-4-yn-1-yloxy)carbonyl]-L-valine:

3-Methyl-N-[(pent-4-yn-1-yloxy)carbonyl]-L-valine was prepared accordingto the procedure for 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine byusing pent-4-yn-1-ol instead of 4-pentenol. LRMS (ESI) m/z 242.2[(M+H)⁺; calcd for C₁₂H₂₀NO₄: 242.1].

Preparation of N-[(hex-5-yn-1-yloxy)carbonyl]-3-methyl-L-valine:

N-[(Hex-5-yn-1-yloxy)carbonyl]-3-methyl-L-valine was prepared accordingto the procedure for 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine byusing hex-5-yn-1-ol instead of 4-pentenol. LRMS (ESI) m/z 256.2 [(M+H)⁺;calcd for C₁₃H₂₂NO₄: 256.1].

Preparation ofN-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valine:

Step 1: N-Isopropylpent-4-en-1-amine

5-Bromo-1-pentene (42.3 mmol) was added to isopropylamine (423 mmol),and the mixture was stirred at 60° C. for 48 h in the dark in a sealedtube. Then the volatiles were evaporated at reduced pressure and thecrude residue was dissloved in 50 mL of diethyl ether and washed twicewith water. The organic phase was dried over Na₂SO₄. Evaporation of thesolvent gave N-isopropylpent-4-en-1-amine as brownish oil (40%) whichwas used without any further purification.

Step 2: MethylN-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valinate

To a solution (60 nM) of L-tert-leucine methyl-ester hydrochloride andNaHCO₃ (8 eq) in dry THF, a solution 20% w/w of phosgene in toluene (5eq) was added dropwise at 0° C. and the reaction mixture was stirred atthat temperature for 30 minutes. Then the solid was filtered-off and thefiltrate evaporated at reduced pressure. The resulting crude yellow oilwas taken-up in dry THF (0.3 M) and added dropwise to a stirred solution(0.2 M) of N-isopropylpent-4-en-1-amine and THF (1 eq). The reactionmixture was stirred at room temperature overnight. Then the mixture wastaken-up in EtOAc and washed twice with water and brine. The organicphase was dried over Na₂SO₄ and the volatiles evaporated at reducedpressure. The crude was purified by flash chromatography eluting withpetroleum ether (8) EtOAc (2) using Nynhydrin as stain. MethylN-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valinate wasobtained as light yellow oil (43%).

Step 3: N-{[Isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valine

To a solution (0.1 M) of methylN-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valinate in a1:1 mixture of water and dioxane, LiOH (4 eq) was added and theresulting mixture was stirred at room temperature for 6 h. The reactionmixture was then concentrated at reduced pressure and the crude residuewas dissolved in EtOAc. The organic phase was washed with water. Theaqueous phase was brought to pH=2 and re-extracted with EtOAc. Afterdrying over Na₂SO₄ and evaporation of the volatiles,N-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valine wasrecovered as a brownish solid (100%) and used without any furtherpurification. LRMS (ESI) m/z 285 [(M+H)⁺; calcd for C₁₅H₂₉N₂O₃: 285.2].

Preparation ofN-{[Hex-5-en-1-yl(isopropyl)amino]carbonyl}-3-methyl-L-valine:

N-{[Hex-5-en-1-yl(isopropyl)amino]carbonyl}-3-methyl-L-valine wasprepared according to the procedure described forN-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valine by using6-bromo-1-hexene in Step 1. LRMS (ESI) m/z 299 [(M+H)⁺; calcd forC₁₆H₃₁N₂O₃; 299.2].

Preparation of3-Methyl-N-{[pent-4-en-1-yl(propyl)amino]carbonyl}-L-valine:

3-Methyl-N-{[pent-4-en-1-yl(propyl)amino]carbonyl}-L-valine was preparedaccording to the procedure described forN-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valine by usingn-propylamine in Step 1. LRMS (ESI) m/z 285 [(M+H)⁺; calcd forC₁₅H₂₉N₂O₃: 285.2].

EXAMPLE 56

HCV NS3 Protease Time-resolved Fluorescence (TRF) Assay

The NS3 protease TRF assay was performed in a final volume of 100 μl inassay buffer containing 50 mM HEPES, pH 7.5, 150 mM NaCl, 15% glycerol,0.15% TRITON X-100, 10 mM DTT, and 0.1% PEG 8000. The NS3 protease waspre-incubated with various concentrations of inhibitors for 10-30minutes. The peptide substrate for the assay isAc—C(Eu)-DDMEE-Abu-[COO]—XSAK(QSY7)-NH2 (SEQ ID NO: 1), where Eu is aneuropium-labeled group, Abu is 1-aminobutanoic acid which connects anester linkage with 2-hydroxy propanoic acid (X). Hydrolysis of thepeptide by NS3 protease activity causes in separation of the fluorophorefrom the quencher, resulting in an increase in fluorescence. Activity ofthe protease was initiated by adding the TRF peptide substrate (finalconcentration 50-100 nM). The reaction was quenched after 1 hour at roomtemperature with 100 μl of 500 mM MES, pH 5.5. Product fluorescence wasdetected using either a VICTOR V2 or FUSION fluorimeter (PERKIN ELMERLife and Analytical Sciences) with excitation at 340 nm and emission at615 nm with 50-400 μs delay. Testing concentrations of different enzymeforms was selected with a signal to background ratio of 10-30. Theinhibition constants were derived using a four-parameter fit.

Compounds in Examples 1-55 were tested to have a Ki value of less than100 nM in the NS3 protease TRF assay as described above.

1. A compound of formula (I):

or a pharmaceutically acceptable salt or hydrate thereof, wherein: p andq are independently 1 or 2; R¹ is CO₂R¹⁰, CONR¹⁰SO₂R⁶, CONR¹⁰SO₂NR⁸R⁹,or tetrazolyl; R² is C₁-C₆ alkyl, C₂-C₆ alkenyl or C₃-C₈ cycloalkyl,wherein said alkyl, alkenyl or cycloalkyl is optionally substituted with1 to 3 halo; R³ is C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkyl(C₁-C₈)alkyl, aryl(C₁-C₈)alkyl, or Het, wherein aryl is phenylor naphthyl and said alkyl, cycloalkyl, or aryl is optionallysubstituted with 1 to 3 substituents selected from the group consistingof halo, OR¹⁰, SR¹⁰, N(R¹⁰)₂, N(C₁-C₆ alkyl)O(C₁-C₆ alkyl), C₁-C₆ alkyl,C₁-C₆ haloalkyl, halo(C₁-C₆ alkoxy), NO₂, CN, CF₃, SO₂(C₁-C₆ alkyl),S(O)(C₁-C₆alkyl), NR¹⁰SO₂R⁶, SO₂N(R⁶)₂, NHCOOR⁶, NHCOR⁶, NHCONHR⁶,CO₂R¹⁰, C(O)R¹⁰, and CON(R¹⁰)₂; Het is a 5- or 6-membered saturatedcyclic ring having 1 or 2 heteroatoms selected from N, O and S, whereinsaid ring is optionally substituted with 1 to 3 substituents selectedfrom halo, OR¹⁰, SR¹⁰, N(R¹⁰)₂, N(C₁-C₆ alkyl)O(C₁-C₆ alkyl), C₁-C₆alkyl, C₁-C₆ haloalkyl, halo(C₁-C₆ alkoxy), NO₂, CN, CF₃, SO₂(C₁-C₆alkyl), S(O)(C₁-C₆ alkyl), NR¹⁰SO₂R⁶, SO₂N(R⁶)₂, NHCOOR⁶, NHCOR⁶,NHCONHR⁶, CO₂R¹⁰, C(O)R¹⁰, and CON(R¹⁰)₂; R⁴ is H, C₁-C₈ alkyl, C₃-C₈cycloalkyl(C₁-C₈)alkyl, or aryl(C₁-C₈)alkyl; wherein aryl is phenyl ornaphthyl and said alkyl, cycloalkyl, or aryl is optionally substitutedwith 1 to 3 substituents selected from the group consisting of halo,OR¹⁰, SR¹⁰, N(R¹⁰)₂, N(C₁-C₆ alkyl)O(C₁-C₆ alkyl), C₁-C₆ alkyl, C₁-C₆haloalkyl, halo(C₁-C₆ alkoxy), NO₂, CN, CF₃, SO₂(C₁-C₆ alkyl),S(O)(C₁-C₆ alkyl), NR¹⁰SO₂R⁶, SO₂N(R⁶)₂, NHCOOR⁶, NHCOR⁶, NHCONHR⁶,CO₂R¹⁰, C(O)R¹⁰, and CON(R¹⁰)₂; R⁵ is H, halo, OR¹⁰, C₁-C₆ alkyl, CN,CF₃, SR¹⁰, SO₂(C₁-C₆ alkyl), C₃-C₈ cycloalkyl, C₃-C₈ cycloalkoxy, C₁-C₆haloalkyl, N(R⁷)₂, aryl, heteroaryl or heterocyclyl; wherein aryl isphenyl or naphthyl, heteroaryl is a 5- or 6-membered aromatic ringhaving 1, 2 or 3 heteroatoms selected from N, O and S, attached througha ring carbon or nitrogen, and heterocyclyl is a 5- to 7-memberedsaturated or unsaturated non-aromatic ring having 1, 2, 3 or 4heteroatoms selected from N, O and S, attached through a ring carbon ornitrogen; and wherein said aryl, heteroaryl, heterocyclyl, cycloalkyl,cycloalkoxy, or alkyl is optionally substituted with 1 to 4 substituentsselected from the group consisting of halo, OR¹⁰, SR¹⁰, N(R⁷)₂, N(C₁-C₆alkyl)O(C₁-C₆ alkyl), C₁-C₆ alkyl, C₁-C₆ haloalkyl, halo(C₁-C₆ alkoxy),C₃-C₆ cycloalkyl, C₃-C₆ cycloalkoxy, NO₂, CN, CF₃, SO₂(C₁-C₆ alkyl),NR¹⁰SO₂R⁶, SO₂N(R⁶)₂, S(O)(C₁-C₆ alkyl), NHCOOR⁶, NHCOR⁶, NHCONHR⁶,CO₂R¹⁰, C(O)R¹⁰, and CON(R¹⁰)₂; wherein 2 adjacent substituents of saidcycloalkyl, cycloalkoxy, aryl, heteroaryl or heterocyclyl, if present,are optionally taken together to form a 3- to 6-membered cyclic ringcontaining 0-3 heteroatoms selected from N, O and S; R⁶ is C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl(C₁-C₅)alkyl, aryl, aryl(C₁-C₄)alkyl,heteroaryl, heteroaryl(C₁-C₄ alkyl), heterocyclyl, or heterocyclyl(C₁-C₈alkyl), wherein said alkyl, cycloalkyl, aryl, heteroaryl, orheterocyclyl is optionally substituted with 1 to 2 W substituents; andwherein each aryl is independently phenyl or naphthyl, each heteroarylis independently a 5- or 6-membered aromatic ring having 1, 2 or 3heteroatoms selected from N, O and S, attached through a ring carbon ornitrogen, and each heterocyclyl is independently a 5- to 7-memberedsaturated or unsaturated non-aromatic ring having 1, 2, 3 or 4heteroatoms selected from N, O and S, attached through a ring carbon ornitrogen; Y is C(═O), SO₂, or C(═N—CN); Z is C(R¹⁰)₂, O, or N(R⁴); M isC₁-C₁₂ alkylene or C₂-C₁₂ alkenylene, wherein said alkylene oralkenylene is optionally substituted with 1 or 2 substituents selectedfrom the group consisting of C₁-C₈ alkyl, C₃-C₈ cycloalkyl(C₁-C₈ alkyl),and aryl(C₁-C₈ alkyl); and 2 adjacent substituents of M, if present, areoptionally taken together to form a 3- to 6-membered cyclic ringcontaining 0-3 heteroatoms selected from N, O and S; each R⁷ isindependently H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆cycloalkyl(C₁-C₅)alkyl, aryl, aryl(C₁-C₄)alkyl, heteroaryl,heteroaryl(C₁-C₄ alkyl), heterocyclyl, or heterocyclyl(C₁-C₈ alkyl),wherein said alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl isoptionally substituted with 1 to 2 W substituents; and wherein each arylis independently phenyl or naphthyl, each heteroaryl is independently a5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selectedfrom N, O and S, attached through a ring carbon or nitrogen, and eachheterocyclyl is independently a 5- to 7-membered saturated orunsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selectedfrom N, O and S, attached through a ring carbon or nitrogen; each W isindependently halo, OR¹⁰, C₁-C₆ alkyl, CN, CF₃, NO₂, SR¹⁰, CO₂R¹⁰,CON(R¹⁰)₂, C(O)R¹⁰, N(R¹⁰)C(O)R¹⁰, SO₂(C₁-C₆ alkyl), S(O)(C₁-C₆ alkyl),C₃-C₈ cycloalkyl, C₃-C₈ cycloalkoxy, C₁-C₆ haloalkyl, N(R¹⁰)₂, N(C₁-C₆alkyl)O(C₁-C₆ alkyl), halo(C₁-C₆ alkoxy), NR¹⁰SO₂R¹⁰, SO₂N(R¹⁰)₂,NHCOOR¹⁰, NHCONHR¹⁰, aryl, heteroaryl or heterocyclyl; wherein aryl isphenyl or naphthyl, heteroaryl is a 5- or 6-membered aromatic ringhaving 1, 2 or 3 heteroatoms selected from N, O and S, attached througha ring carbon or nitrogen, and heterocyclyl is a 5- to 7-memberedsaturated or unsaturated non-aromatic ring having 1, 2, 3 or 4heteroatoms selected from N, O and S, attached through a ring carbon ornitrogen; R⁸ is C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyl(C₁-C₈alkyl), aryl, aryl(C₁-C₄ alkyl), heteroaryl, heterocyclyl,heteroaryl(C₁-C₄ alkyl), or heterocyclyl(C₁-C₈ alkyl), wherein saidalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionallysubstituted with 1 to 4 substituents selected from the group consistingof aryl, C₃-C₈ cycloalkyl, heteroaryl, heterocyclyl, C₁-C₆ alkyl,halo(C₁-C₆ alkoxy), halo, OR¹⁰, SR¹⁰, N(R¹⁰)₂, N(C₁-C₆ alkyl)O(C₁-C₆alkyl), C₁-C₆ alkyl, C(O)R¹⁰, C₁-C₆ haloalkyl, NO₂, CN, CF₃, SO₂(C₁-C₆alkyl), S(O)(C₁-C₆ alkyl), NR¹⁰SO₂R⁶, SO₂N(R⁶)₂, NHCOOR⁶, NHCOR⁶,NHCONHR⁶, CO₂R¹⁰, and C(O)N(R¹⁰)₂; wherein each aryl is independentlyphenyl or naphthyl; each heteroaryl is independently a 5- or 6-memberedaromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S,attached through a ring carbon or nitrogen; and each heterocyclyl isindependently a 5- to 7-membered saturated or unsaturated non-aromaticring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, attachedthrough a ring carbon or nitrogen; and wherein 2 adjacent substituentsof said cycloalkyl, cycloalkoxy, aryl, heteroaryl or heterocyclyl, ifpresent, are optionally taken together to form a 3- to 6-membered cyclicring containing 0-3 heteroatoms selected from N, O and S; R⁹ is C₁-C₈alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyl(C₁-C₈ alkyl), C₁-C₈ alkoxy,C₃-C₈ cycloalkoxy, aryl, aryl(C₁-C₄ alkyl), heteroaryl, heterocyclyl,heteroaryl(C₁-C₄ alkyl), or heterocyclyl(C₁-C₈ alkyl), wherein saidalkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, heteroaryl or heterocyclylis optionally substituted with 1 to 4 substituents selected from thegroup consisting of aryl, C₃-C₈ cycloalkyl, heteroaryl, heterocyclyl,C₁-C₆ alkyl, halo(C₁-C₆ alkoxy), halo, OR¹⁰, SR¹⁰, N(R¹⁰)₂, N(C₁-C₆alkyl)O(C₁-C₆ alkyl), C₁-C₆ alkyl, C(O)R¹⁰, C₁-C₆ haloalkyl, NO₂, CN,CF₃, SO₂(C₁-C₆ alkyl), S(O)(C₁-C₆ alkyl), NR¹⁰SO₂R⁶, SO₂N(R⁶)₂, NHCOOR⁶,NHCOR⁶, NHCONHR⁶, CO₂R¹⁰, and C(O)N(R¹⁰)₂; wherein each aryl isindependently phenyl or naphthyl; each heteroaryl is independently a 5-or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected fromN, O and S, attached through a ring carbon or nitrogen; and eachheterocyclyl is independently a 5- to 7-membered saturated orunsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selectedfrom N, O and S, attached through a ring carbon or nitrogen; and wherein2 adjacent substituents of said cycloalkyl, cycloalkoxy, aryl,heteroaryl or heterocyclyl, if present, are optionally taken together toform a 3- to 6-membered cyclic ring containing 0-3 heteroatoms selectedfrom N, O and S; or R⁸ and R⁹ are optionally taken together, with thenitrogen atom to which they are attached, to form a 4- to 8-memberedmonocyclic ring containing 0-2 additional heteroatoms selected from N, Oand S; and each R¹⁰ is independently H or C₁-C₆ alkyl.
 2. The compoundof claim 1, wherein the compound is of formula III:

or a pharmaceutically acceptable salt or hydrate thereof, wherein thesum of p and q is ≦3.
 3. The compound of claim 2, wherein R¹ is CO₂R¹⁰,CONR¹⁰SO₂R⁶ or CONHSO₂NR⁸R⁹.
 4. The compound of claim 3, wherein R¹ isCONHSO₂R⁶.
 5. The compound of claim 4, wherein R⁶ is C₃-C₈ cycloalkyl.6. The compound of claim 3, wherein R¹ is CONHSO₂NR⁸R⁹ wherein R⁸ isC₁-C₃ alkyl and R⁹ is C₁-C₃ alkyl or —(CH₂)₁₋₂-phenyl.
 7. The compoundof claim 3, wherein R² is C₂-C₄ alkenyl.
 8. The compound of claim 7,wherein R³ is C₅-C₆ cycloalkyl optionally substituted with C₁-C₆ alkylor C₁-C₈ alkyl optionally substituted with 1 to 3 substituents selectedfrom halo and OR¹⁰.
 9. The compound of claim 8, wherein R⁵ is H, halo orC₁-C₆ alkoxy.
 10. The compound of claim 9, wherein Y is C═O.
 11. Thecompound of claim 10, wherein Z is O, C(R¹⁰)₂, NH or N(C₁-C₈ alkyl). 12.The compound of claim 11, wherein M is unsubstituted C₄-C₈ alkylene orunsubstituted C₄-C₈ alkenylene.
 13. The compound of claim 1, wherein thecompound is selected from the group consisting of compounds III-1 toIII-240, or a pharmaceutically acceptable salt or hydrate thereof:


14. The compound of claim 1, wherein: p and q are both 1; R¹ isCONR¹⁰SO₂R⁶; R² is C₁-C₆ alkyl or C₂-C₆ alkenyl; R³ is C₅-C₆ cycloalkylor C₁-C₈ alkyl optionally substituted with 1 to halo substitutents; R⁵is H, F or Cl; R⁶ is C₃-C₆ cycloalkyl; Y is C(═O); Z is O, CH₂, NH orN(CH₃); M is C₁-C₈ alkylene or C₂-C₈ alkenylene, wherein said alkyleneor alkenylene is optionally substituted with 1 or 2 substituentsselected from the group consisting of C₁-C₈ alkyl, C₃-C₈cycloalkyl(C₁-C₈alkyl) or aryl(C₁-C₈alkyl), and 2 adjacent substituentsof M, if present, are optionally taken together to form a 3- to6-membered cyclic ring containing 0-2 heteroatoms selected from N, O,and S; and R¹⁰ is H or C₁-C₆ alkyl.
 15. The compound of claim 14,wherein the compound is of formula III-a:

or a pharmaceutically acceptable salt or hydrate thereof.
 16. Thecompound of claim 15, wherein R⁶ is cyclopropyl.
 17. The compound ofclaim 16, wherein R² is C₁-C₄ alkyl or C₂-C₄ alkenyl.
 18. The compoundof claim 17, wherein R³ is C₅-C₆ cycloalkyl or C₁-C₄ alkyl.
 19. Thecompound of claim 18, wherein M is either


20. A pharmaceutical composition comprising an effective amount of acompound of any one of claims 1, 2, 13, 14, or 15, and apharmaceutically acceptable carrier.
 21. The pharmaceutical compositionof claim 20, further comprising a second therapeutic agent selected fromthe group consisting of a HCV protease inhibitor and HCV NS5B polmeraseinhibitor.
 22. A method of inhibiting HCV NS3 protease activity in asubject in need thereof, said method comprising administering to saidsubject an effective amount of the compound of any one of claims 1, 2,13, 14 or
 15. 23. A method of preventing or treating infection by HCV ina subject in need thereof, said method comprising administering to saidsubject an effective amount of the compound of any one of claims 1, 2,13, 14 or
 15. 24. The method of claim 23, wherein said method furthercomprises administering at least one second therapeutic agent selectedfrom the group consisting of a HCV antiviral agent, an immunomodulator,and an anti-infective agent.
 25. The method of claim 24, wherein the HCVantiviral agent is an antiviral selected from the group consisting of aHCV protease inhibitor and a HCV NS5B polymerase inhibitor.
 26. Acompound selected from the group consisting of:

or a pharmaceutically acceptable salt or hydrate thereof.
 27. Apharmaceutical composition comprising an effective amount of thecompound of claim 26 and a pharmaceutically acceptable carrier.
 28. Thepharmaceutical composition of claim 27, further comprising a secondtherapeutic agent selected from a HCV protease inhibitor and a HCV NS5Bpolymerase inhibitor.
 29. A method of inhibiting HCV NS3 proteaseactivity in a subject in need thereof, said method comprisingadministering to said subject an effective amount of the compound ofclaim
 26. 30. A method of preventing or treating infection by HCV in asubject in need thereof, said method comprising administering to saidsubject an effective amount of the compound of claim
 26. 31. The methodof claim 30, wherein said method further comprises administering atleast one second therapeutic agent selected from the group consisting ofa HCV antiviral agent, an immunomodulator, and an anti-infective agent.32. The method of claim 31, wherein the HCV antiviral agent is anantiviral selected from the group consisting of a HCV protease inhibitorand a HCV NS5B polymerase inhibitor.
 33. The compound of claim 26,wherein said compound is

or a pharmaceutically acceptable salt thereof.
 34. A pharmaceuticalcomposition comprising an effective amount of the compound of claim 33and a pharmaceutically acceptable carrier.
 35. A method of inhibitingHCV NS3 protease activity in a subject in need thereof, said methodcomprising administering to said subject an effective amount of thecompound of claim
 33. 36. A method of preventing or treating infectionby HCV in a subject in need thereof, said method comprisingadministering to said subject an effective amount of the compound ofclaim
 33. 37. The compound of claim 26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 38. A pharmaceuticalcomposition comprising an effective amount of the compound of claim 37and a pharmaceutically acceptable carrier.
 39. A method of inhibitingHCV NS3 protease activity in a subject in need thereof, said methodcomprising administering to said subject an effective amount of thecompound of claim
 37. 40. A method of preventing or treating infectionby HCV in a subject in need thereof, said method comprisingadministering to said subject an effective amount of the compound ofclaim 37.